Postoperative Pain Management, AN EVIDENCE-BASED GUIDE TO PRACTICE

24 • Postoperative Pain Management for Patients with Drug Dependence 243 produces a sense of well-being, but higher doses can lead to withdrawal depends on the drug of dependence. Because depression, panic, and psychosis. Abstinence from marijuana dopamine seems to play a role in the neurobiological reward is not known to cause a physical withdrawal syndrome. system, efforts have been made to develop drugs that modify However, patients may experience psychological cravings the dopaminergic system. For example, bupropion, which for this drug. These patients may exhibit restlessness, anxiety, increases dopamine and noradrenaline levels in the synaptic and insomnia when they stop using marijuana. Long-term cleft, has been found to be effective in treating nicotine use of this drug can cause memory problems.39 addiction.42 SUMMARY ALCOHOL ABUSE Because addiction is considered a chronic and persistent Alcoholics have been treated with disulfiram, which disease, and because patients who have been addicted to inhibits aldehyde dehydrogenase and causes acetaldehyde substances are prone to recurrence of addictive behaviors, it is accumulation in patients who ingest alcohol. This accumu- possible that exposure to drugs of abuse during the periopera- lation causes a severely unpleasant reaction. Disulfiram also tive period may rekindle a latent addictive state. In individuals inhibits dopamine β-hydroxylase, possibly leading to an atten- who previously abused substances, changes may have devel- uated cardiovascular response during anesthesia.10 Disulfiram oped in the neural circuitry involving dopaminergic neurons can inhibit hepatic systems that are responsible for metabolism located in the brain. Because of the possibility of cross- of drugs such as barbiturates, tricyclic antidepressants, and addiction, exposure to an opioid or benzodiazepine may stim- warfarin.43 ulate cravings and other addictive behaviors, even in patients who had previously abused nonopioids such as alcohol and Patients who have abused alcohol can be treated with cocaine. μ opioid receptor antagonists such as naltrexone and nalme- fene. These drugs reduce cravings for alcohol and, when an Maintaining abstinence from drugs of abuse is a complex opioid is taken, increase the dose of opioid required to produce process that depends not only on overcoming physical with- euphoria.44 To simplify postoperative management, opioid drawal from substances but also on developing social and antagonists should be stopped before surgery. If these drugs coping mechanisms to avoid recrudescence.10 Psychotherapy are continued during the perioperative period, patients will and behavioral modification programs may be helpful in this probably require higher doses of opioids to achieve analgesia. regard, including programs such as Alcoholics Anonymous Other drugs that have been used to reduce cravings for alco- and Narcotics Anonymous. Individuals who participate in hol are acamprosate and anticonvulsant medications, such these programs and who have pledged abstinence from as carbamazepine, valproate, and gabapentin.45–47 In alcohol drugs may understandably have anxiety about whether they withdrawal, increased NMDA function occurs, and acam- will be exposed to substances of abuse during the perioper- prosate, which antagonizes the NMDA receptor, has been ative period. In some cases, patients refuse anxiolytics or shown to double abstinence rates.35 Antidepressants in the opioids, especially while awake before surgery, and prefer to selective serotonin reuptake inhibitor class, such as fluoxetine, use cognitive and behavioral strategies to relieve preoperative and anxiolytics such as buspirone can reduce alcohol drinking anxiety. Unfortunately, there have been reports of patients in patients who are depressed or anxious.48,49 experiencing addiction relapse after being exposed to opi- oids given perioperatively.10,40 Greater stress, anxiety, and OPIOID ABUSE poorly treated pain can all lead to requests for higher doses of opioids postoperatively,41 even in patients whose addiction The μ receptor subtype seems to play a key role in mediating illness is in remission. cravings and reward in opioid abuse. Mice who lack this receptor exhibit no reinforcing behaviors for continuing to The perioperative management of patients who are prone take morphine.50 Drugs that are antagonists at the μ receptor, to addiction must recognize that patients may be taking cer- such as naltrexone, have been used to treat opiate addiction. tain drugs to prevent relapse. These include disulfiram for The effects of drugs that inhibit the NMDA receptor, such alcoholics, acamprosate (reduces “reward” in alcoholics), as ketamine and memantine, may decrease opioid-induced naltrexone (opioid antagonist, also used for alcoholics), and tolerance. methadone or buprenorphine (drug substitution for μ opioid receptor agonists). It is also important to understand that Opiate withdrawal is accompanied by activation of the there is a higher incidence of psychiatric disorders in patients sympathetic nervous system. When opioids are discontinued, who have had substance abuse problems, including anxiety, adrenergic activation of the locus ceruleus neurons in the brain depression, and psychosis, and that such patients may be is seen.51 Manifestations of increased noradrenergic activity taking a variety of pharmacological treatments with anesthetic can be treated with α2 agonists, such as clonidine, lofexidine, and postoperative consequences.10 and tizanidine. These drugs have been shown to modulate withdrawal symptoms and decrease the sympathomimetic Treatments for Drug Dependence response to withdrawal. However, they may also cause hypo- and Addiction tension, sedation, and bradycardia, although these side effects are less likely with tizanidine and lofexidine. A number of pharmacological, psychological, and behavioral treatments have been proposed to manage patients with sub- Because cravings for opiate drugs are greater when short- stance abuse disorders and drug addiction. Management of acting opiates are used, the use of methadone and buprenor- phine, which have long half-lives, for the treatment of opioid addiction has been growing. Methadone is a full agonist at

244 SECTION IV • Postoperative Pain Management in Specific Clinical Settings the μ receptor, but it may also have NMDA receptor antag- Perioperative Plan for the Drug- onistic activity. Buprenorphine (Subutex) is a partial opioid Dependent Patient agonist at the μ receptor and a κ receptor antagonist. Stimulation of κ receptors has been found to reduce dopamine One of the most common challenges in the perioperative levels and produce aversive responses.13 Buprenorphine is management of a drug-dependent patient is developing a also available in combination with naloxone, which is a μ treatment plan for a patient who is opioid tolerant. Patients receptor antagonist; this drug combination is called Suboxone. who are opioid tolerant may be using prescription opioids The peak effect of buprenorphine is at 100 minutes, and for the management of chronic or cancer pain, or they may the effects return to baseline at 48 hours, with a half-life of be abusing prescription opioids or other opioid-type drugs. 37 hours. It is usually prescribed as a single daily dose of Although there are similarities in managing patients who are 16 mg, given sublingually. Because buprenorphine is a par- tolerant to opioids regardless of their addiction status, there tial agonist at the μ receptor, it gives a lower level of response are additional considerations for the management of patients at maximal receptor occupancy and it exhibits a “ceiling who both are dependent on opioids physiologically and have effect.” However, because of its analgesic effects, some prac- substance abuse problems. In either case, the issue of opioid titioners use it as an analgesic drug. Comparisons of the use tolerance in the perioperative period needs to be considered. of buprenorphine to methadone have shown similar results A good treatment plan will address problems with acute in the treatment of opiate addiction. Weaning programs for pain after surgery, ongoing chronic pain, and psychological methadone often involve decreasing the dose by as little as issues that may be affecting the patient. 3% per week to as much as 5% per day. LAAM (L-acetyl-α methadol) is an alternative long-acting μ receptor agonist. PREPARING A TREATMENT PLAN In patients who take any of these μ agonist-type drugs, Whenever possible, it is important to prepare a plan for pain the usual doses should be continued in the postoperative management for opioid-dependent surgical patients before period. Otherwise, withdrawal may result, and increased pain surgery. Preoperatively, there should be an agreement on which is likely. Substituting these drugs for other opioids in the service will be primarily responsible for managing pain, and all perioperative period only complicates management, in terms caregivers should achieve consensus on the treatment plan. of both addiction control and analgesia. Similarly, using This may necessitate that the surgical service consult with a addiction-management drugs as analgesics and raising their pain management specialist prior to surgery. The care team doses makes it more difficult to return to their intended use should be aware that the patient’s opioid dependence makes after the patient has recovered from surgery. Management is it more likely that the patient’s pain will be undertreated post- simplified by maintaining agonist drugs used for addiction operatively if precautions are not taken. Negative attitudes at their standard doses and using additional intravenous or on the part of caregivers, educational deficiencies, and simple short-term oral analgesics for acute pain after surgery. reluctance to prescribe drugs to a “recovering” addict may lead to poorly controlled pain. In addition, poorly treated pain OTHER ADDICTIONS can result in greater anxiety for the patient, along with low self-esteem and depression. Patients should be reassured The endocannabinoid system, of which the CB-1 receptor is that their history of substance abuse will not be a barrier to found in the brain, may play a role in the reward and cravings their receiving appropriate pain management after surgery.10 mechanism for various drugs, nicotine, and food. Long-term For those patients in substance abuse treatment programs, it tobacco use has been found to stimulate the CB-1 receptor, is prudent to confer with the mental health provider in order and the reward response to morphine is reduced in mice to optimize the perioperative plan. lacking CB-1 receptors. Various cannabinoids have been found to increase the efflux of dopamine in the nucleus accumbens.52 Although less likely, it is possible that a patient will receive Rimonabant, which blocks the CB-1 receptor, has been inappropriately high doses of opioids in the postoperative shown to decrease cravings for food and nicotine, and drugs period and that he or she may engage in manipulative behav- in this class may play a promising role in the management ior to obtain excessive doses of opioids. The care team should of opioid addiction. keep in mind the planned surgical procedure and the antic- ipated levels of pain that may result. Continued use of an From a psychological perspective, addictive drugs can pro- opioid postoperatively should be determined by the clinical duce euphoria, which acts as a positive reinforcer, stimulating picture of the patient after surgery. Preoperatively, an outline further use. Similarly, taking addictive drugs can relieve symp- should be prepared specifying what interventions may be toms of dysphoria or withdrawal, which are negative rein- necessary for poorly controlled pain, and a strategy for taper- forcers and which also increase the motivational drive to obtain ing opioid doses postoperatively should be discussed with the drug. Cues in the environment can stimulate a conditioned the patient. response, such as cravings, which promotes further drug use.13 Therefore, the reward system in the brain can become sensi- PREOPERATIVE PERIOD tized to environmental stimuli that are independent of physical withdrawal symptoms and that lead to increased drug use. In the preoperative period, patients who take opioids regularly Patients with risk-taking behaviors and psychiatric disorders should be identified, and opioid-dependent or opioid-tolerant are especially prone to abuse behaviors.53,54 Therefore, cogni- patients should be designated for special perioperative con- tive-behavior therapies that focus on this type of aberrant sideration. All patients should be questioned as to whether behavior may play a role in the perioperative period in deter- mining a treatment plan for the drug-dependent patient.

24 • Postoperative Pain Management for Patients with Drug Dependence 245 they have previous or current history of using alcohol, tobacco, be measured in terms of cardiovascular responses to pain and, opioids, benzodiazepines, and all other prescribed or illicit for those patients who are spontaneously breathing, changes drugs that can cause dependence. Specifically, patients should in respiratory rates. Patients with increasing respiratory rates be interviewed to determine what dose of opioids they are may require supplementation of intraoperative opioid. In taking and over what period they have taken opioid drugs. addition, patients may benefit from the use of epidural or In patients whose veracity is suspect, urine toxicology testing regional anesthesia to decrease nociceptive input from the may play a role. Previous histories of surgical procedures and area of surgery. They will be less likely to experience the postoperative recovery should be obtained, with a focus on adverse effects of high doses of opioids, such as respiratory how the patient fared in terms of pain control. Intolerances depression. The anesthesia care team should communicate to or experience of side effects to particular opioids should the patient’s intraoperative opioid requirements and preoper- be identified. If the patient has a chronic pain syndrome, a ative opioid use history to the postoperative care team, which description of the pain should be documented as well as may include staff in the post-anesthesia care unit as well as how well the pain responds to the current opioid treatment. on the hospital floor or in the intensive care unit. This level of communication is important for all opioid-dependent Once the baseline pain management history is obtained, patients and is especially vital if the patient is expected to options for postoperative pain control should be delineated remain intubated or pharmacologically paralyzed. and discussed with the patient. It is important to understand the patient’s expectations about postoperative pain control POSTOPERATIVE MANAGEMENT and to educate the patient about the expected course of surgery and recovery. The perioperative team should be aware of a In the postoperative period, patients who are opioid depend- patient’s underlying chronic pain. Patients who report high ent may experience higher levels of pain. This may occur levels of pain preoperatively will probably report higher levels because preexisting analgesic use leads to increased postop- of pain (visual analogue scale [VAS] scores) both before and erative requirements, tolerance to opioid drugs, and perhaps after surgery. The treatment team may need to use alternative decreased efficacy of therapy. In some cases, caregivers under- measurement scales to obtain an accurate picture of the sever- utilize analgesics.56 In a review of 3058 postoperative patients, ity of postoperative pain in these patients. Rapp et al55 found that 6.6% of patients had a history of long- term opioid use prior to surgery. Patients who used opioids DAY OF SURGERY before surgery were found to consume more opioid (24-hour usage = 135.8 mg morphine equivalent) via PCA postoper- On the day of surgery, patients who routinely take sustained- atively compared to opioid-naive patients (24 hour usage release opioids should take their usual dose of medication. = 42.8 mg morphine equivalent). In spite of higher opioid Duration of action for most of these drugs is 8 to 24 hours, usage, pain scores (VAS scores 0–10) were higher in the long- or even 72 hours for transdermal fentanyl. Therefore, having term opioid use group than in the opioid-naive group, both the patient take such a drug just prior to surgery enables base- at rest (VAS 5 versus 3) and with movement (VAS 8 versus 6). line analgesic levels to be maintained during surgery and in Medications for anxiety were ordered postoperatively for 18.7% the immediate postoperative period. Patients who neglect to of the long-term opioid use group, compared with 0.6% of take their usual opioids before surgery can be supplemented the opioid-naive group. The long-term opioid use group tended with intravenous formulations during surgery. to use PCA longer (4 days versus 3) and had a lower incidence of nausea and pruritus related to opioid therapy. Patients Because pain management may be more challenging for with nonmalignant pain had higher opioid consumption those who are tolerant to opioids, it is appropriate to counsel and pain scores than those with a cancer diagnosis. Factors patients on the possibility that their pain levels may be more such as anxiety and depression, which are more prevalent in difficult to control. Correcting unreasonable expectations, the chronic pain population, may also play a role in reports such as being completely pain free after major surgery, may of higher postoperative pain in these patients. When patients decrease postoperative levels of anxiety in some patients and attach a negative meaning to a surgical procedure, higher reduce the dissatisfaction that may result from false hopes. doses of analgesics may be used.57 In addition to opioid toler- Patients should be educated on the various methods to control ance and seeming loss of efficacy, it may be that patients with pain postoperatively, including the use of patient-controlled chronic pain who use opioids have negative perceptions of analgesia (PCA), epidural and regional anesthetic tech- surgery that promote anxiety and fear and instigate higher niques, and adjuvant medications such as anxiolytics, anti- opioid consumption. inflammatories, and others. Depending on the type of surgery and expected recovery, patients may not be able to take their One reason that a long-term opioid user is undertreated chronic pain medications orally, and alternative routes should after surgery is that the patient’s usual preoperative baseline be considered and prepared for. Patients should be allowed dose of opioid is not continued. In some cases, patients are to take their usual analgesic drugs up to the time of surgery, unable to take oral preparations immediately after surgery or along with other preoperative medications, often with a sip the treatment team does not implement these prescriptions on of water. a routine basis. Patients receiving long-term opioid therapy must resume their usual dose of opioid so that they continue INTRAOPERATIVE ISSUES to take baseline levels during their hospitalization. An excep- tion to this rule would be the patient whose operation is Patients who are opioid dependent or opioid tolerant may expected to reduce his or her chronic pain. In most patients require higher doses of analgesic drugs as part of their intra- who are opioid dependent, a preexisting prescription for operative anesthetic management.16,55 Patient response may

246 SECTION IV • Postoperative Pain Management in Specific Clinical Settings transdermal patches or oral opioids should be continued There may be improvements in functional activities when throughout the postoperative period; if they cannot take low-dose local anesthetic infusions are used. Also, spinal medications orally, their oral opioid regimen should be con- and epidural opiates have greater potency than opiates given verted into a basal infusion of intravenous opioids, usually via the oral or intravenous route. Therefore, reduced side at about 50% of the dose equivalent, with supplemental effects of opioid therapy may be realized. However, it is doses provided as needed. unknown whether the use of regional techniques or spinal opiates in the perioperative period decreases drug cravings Another reason patients who are opioid dependent may or relapse of addiction in opioid-dependent patients.10 Even experience additional pain after surgery is their tolerance to if a regional technique is used, continuation of preoperative opioid drugs. Tolerance may necessitate that higher doses of opioids for such patients will probably be needed, at least at opioid be given both intraoperatively and postoperatively to a portion of their long-term dose, to prevent withdrawal prevent pain. Therefore, it may take both a baseline dose of reactions or chronic pain that may exist outside of the area opioid and a higher intermittent dose of opioid to achieve of regional analgesia. Pain relief will be optimized if patients analgesia in the opioid-dependent patient. Because tolerance who take opioids long term are permitted to continue at to opioids can develop even after short-term use (days or their usual doses. Complete discontinuation of opiates may weeks), even patients receiving brief courses of preoperative result in significant pain complaints even in the setting of opioids should be monitored for signs and symptoms of opioid excellent regional anesthetic blockade. If there is a concern tolerance. Patients who are tolerant to opioids are more likely about excessive sedation, patients may be given approxi- to experience increased pain and to require higher doses of mately 50% of their baseline doses of opioid, at which level opioids to relieve pain after surgery.16 In some patients, withdrawal reactions are unlikely. In any case, frequent long-term tolerance develops, so that patients are relatively reassessment of such patients and adjustment of doses may insensitive to the effects of opioids even years after they have be necessary to achieve optimal pain control. discontinued use. This phenomenon may be related to changes in neuronal plasticity, activation of NMDA receptors In addition to regional anesthetic techniques, the use of and glutamate, and greater production of spinal dynorphin, adjuvant drugs can decrease opioid requirements in the an endogenous opioid peptide.16 postoperative period. Nonsteroidal anti-inflammatory drugs (NSAIDs) can provide additional analgesia to that achieved If a patient can resume oral intake within several hours using with morphine alone in the postoperative setting after surgery, the baseline dose of orally administered chronic (although NSAID administration alone is usually inade- opioid therapy should be resumed. In addition, either an oral quate). Such agents can be effective in reducing the amount opioid or an intravenous PCA system should be imple- of opioid consumed and therefore result in a lower incidence mented. For both oral and intravenous opioids, the intermit- of opioid-related side effects after surgery. They can also tent dose may need to be higher to account for opioid provide additional analgesia to persons with particular types tolerance, and this can be delivered via a PCA device. To of pain, such as bony or musculoskeletal pain. However, reduce the effects of tolerance, it may be advantageous to use the use of NSAIDs may be associated with gastrointestinal an opioid different from the one the patient is accustomed to. injury, renal problems, bleeding complications, cardiovascu- Because of interindividual variability in response to different lar complications, and delayed bone healing. For refractory opioids, changing from one opioid to another may provide pain in an opioid-resistant patient, ketamine has been used better analgesia with fewer side effects in some patients.58 with some success.60 An NMDA-antagonist, ketamine is known to enhance opioid analgesia, and its administration If a patient is unable to take opioids orally, the preopera- can reduce tolerance to opioid drugs. Finally, patients with tive opioid dose should be converted into an equipotent excessive anxiety and fear related to surgery may benefit intravenous dose, and 50% of it may be given as a baseline from the judicious use of benzodiazepines in the postoperative continuous intravenous infusion. If necessary, patients can period, with care taken to avoid oversedation. use a PCA system to meet the remainder of their opioid requirement postoperatively. This technique allows optimal After surgery, once the patient’s gastrointestinal function titration of analgesics to effect and reduces delays and anxi- has recovered, an oral analgesic regimen can be recom- ety related to potential withholding of analgesics. Although menced. Again, if the patient had been taking a sustained- there is some concern that use of a PCA device may reinforce release preparation of an opioid for chronic pain, this should reward behaviors in addicts,59 the use of PCA can reduce the be continued at its preoperative dose if chronic pain is still risk of inadequate medication, and the probability that this an issue. For additional “as-needed” pain relief, patients may modality would lead to an addiction problem is low. In case be given a standard short-acting opioid such as oxycodone, the predicted doses used in PCA are inadequate, an order for morphine, or hydromorphone. The patient who is tolerant “rescue” doses should be implemented. These can be twice to opioids may require higher doses of “as-needed” medica- the level of “as-needed” patient-controlled doses. Repeated tions in the immediate postoperative period. A tapering rescue doses should be permitted for the patient after eval- schedule based on the level of pain and the type of surgery uation by a nurse. In patients who use transdermal patches performed should be outlined for such a patient. for analgesia, the patches should be continued in the post- operative period. Because hyperthermia can cause greater Dosages of postoperative pain medications in an opioid- absorption of some transdermal medications, patients who dependent patient should be tapered over the same time demonstrate postoperative fevers may receive unexpectedly span as opioids would be reduced in an opioid-naive patient higher doses of opioids, and caregivers should be alerted to after surgery. The treatment team must be alert for signs of this possibility. abnormal drug-seeking behavior or loss of control over the reasonable use of postoperative analgesics. However, oral Patients who receive regional or epidural techniques for opioid doses may be higher in opioid-tolerant patients than pain control may have lower needs for systemic opioids.

24 • Postoperative Pain Management for Patients with Drug Dependence 247 in opiate-naive patients. Dosage tapering can be continued take pure μ antagonist drugs should discontinue use of such on an outpatient basis until the preoperative baseline dose drugs at least 24 hours before surgery. Otherwise, it may be of opioid used for chronic pain is reached. This process may difficult to titrate opioids necessary for postoperative pain take 1 to 2 months. Caregivers should avoid escalating the control; the antagonist drugs may impede the analgesic chronic pain medication dose to supplement acute postop- activity of μ agonists given for pain relief. For patients who erative opioid needs. Limited-quantity prescriptions should take a mixed agonist-antagonist, there will be a ceiling effect be dispensed, and a reasonable tapering schedule should be to analgesia with these drugs. The drugs can competitively outlined. After discharge, the patient should be given an bind to μ receptors (because they are μ receptor antagonists) appointment with the pain management center to follow up and block the action of μ agonists given postoperatively. on the course of drug tapering. More frequent follow-up and Some practitioners have reported using supplemental monitoring allow better evaluation of recovery and medica- μ agonist drugs as analgesics for patients who are taking tion use as well as assessment of whether a transition to partial-agonist regimens, such as buprenorphine (which is inappropriate use of analgesics is occurring. In some cases, a partial μ agonist, having a ceiling effect for its μ agonism), dispensing of postoperative analgesics by a family member with some improvement in pain control. Although this may reduce the chances of loss of control for the substance- method of treatment may be adequate for patients after abusing patient. minor surgery, it is unlikely to be effective for patients who undergo surgery that is likely to produce more severe pain. Postoperative Pain Management in the A more prudent course would be to replace the mixed Addicted Patient agonist-antagonist drug or the partial μ agonist drug with a full μ receptor agonist drug about 48 to 72 hours preopera- Use of addictive drugs can produce permanent alterations tively and then resume the mixed drug after the acute phase in the neurobiology of the brain. These changes can cause of recovery has been completed. Usually, the original agent cravings for drugs and lead to relapse of addiction even years can be resumed within 5 to 7 days of major surgery. The goal after a patient has stopped using the drug.14 This process should be to return the patient to the baseline drug regimen may make weaning from opioids after surgery particularly as soon as possible. difficult for these patients. Exposure to psychological stress, environmental stimuli previously associated with drug use, Conclusion or reexposure to the drug itself can cause a relapse of addic- tive behaviors. The likelihood of relapse may vary among Managing drug-dependent patients in the perioperative patients and with the different drugs used. With opioid use, period may be complicated by the physical and psychologi- elevations of certain subtypes of glutamate receptors found cal nature of the substance use issue. Unfortunately, there in the brain may be responsible for relapse.61 Long-term treat- are no prospective studies of suggested best practices. It is ment with morphine may increase the expression of tran- important to avoid undermedicating or overmedicating scription factors and genes in mesolimbic structures, leading these challenging patients. to a behavioral sensitization to addictive substances.14,15 Finally, exposure to opioids can cause structural changes in In addition to understanding the basic concepts of post- brain neurons. Behavioral sensitization to opioids, along with operative pain management, one must have knowledge of neurobiological and structural factors, can be long lasting the neural and behavioral basis of addiction. Acquiring such and persist for months or years. An individual with a history knowledge may require consultations with specialists in of substance abuse may therefore be prone to cravings and addiction medicine as well as chronic pain. 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Davis KM, Wu JY: Role of glutaminergic and GABAergic systems in alcoholism. J Biomed Sci 2000;8:7–19. 53. Helmus TC, Downey KK, Arfken CL, et al: Novelty seeking as a predictor of treatment retention for heroin dependent cocaine users. 26. Lejoyeaux M, Solomon J, Ades J: Benzodiazepine treatment for alcohol- Drug Alcohol Depend 2001;61:287–295. dependent patients. Alcohol Alcohol 1998;33:563–575. 54. Kavanaugh DJ, McGrath J, Saunders JB, et al: Substance misuse in 27. Adinoff B: Double-blind study of alprazolam, diazepam, clonidine, and patients with schizophrenia: Epidemiology and management. Drugs placebo in the alcohol withdrawal syndrome: preliminary findings. 2002;62:743–755. Alcohol Clin Exp Res 1994;18:873–878. 55. Rapp S, Ready B, Nessly M: Acute pain management in patients with 28. Weiss F, Porrino LJ: Behavioral neurobiology of alcohol addiction: prior opioid consumption: A case-controlled retrospective review. Pain Recent advances and challenges. J Neurosci 2002;22:3332–3337. 1995;61:195–201. 29. Kosten TR, O’Connor PG: Management of drug and alcohol withdrawal. 56. Hamilton J, Edgar L: A survey examining nurses’ knowledge of pain N Engl J Med 2003;348:1786–1795. control. J Pain Symptom Manag 1992;7:18–26. 30. Rickels K, DeMartinis N, Rynn M, et al: Pharmacologic strategies for 57. Chapman CR, Cox GB: Anxiety, pain and depression surrounding discontinuing benzodiazepine treatment. J Clin Psychopharm elective surgery: A multivariate comparison of abdominal surgery 1999;19(Suppl 2):12S–16S. patients with kidney donors and recipients. J Psychosom Res 21;1977: 7–15. 31. Griffiths RR, Wolf B: Relative abuse liability of different benzodi- azepines in drug abusers. J Clin Psychopharmacol 1990;10:237–243. 58. Woodhouse A, Ward EM, Mather LE: Intra-subject variability in post-operative patient-controlled analgesia (PCA): Is the patient 32. Janssen Pharmaceutical Company: Memo, received November 14, equally satisfied with morphine, pethidine and fentanyl? Pain 1999;80: 2004. 545–553. 33. Fishbain DA, Rosomoff HL, Rosomoff RS: Drug abuse, dependence, 59. Beattie C, Umbricht-Schneiter A, Mark L: Anesthesia and analgesia. In and addiction in chronic pain patients. Clin J Pain 1992;8:77–85. Graham AW, Schultz TK (eds): Principles of Addiction Medicine, 2nd ed. Chevy Chase, Md: American Society of Addiction Medicine, 1998, 34. Boot BP, McGregor IS, Hall W: MDMA (Ecstasy) neurotoxicity: Assessing pp 877-890. and communicating the risks. Lancet 2000;355:1818–1821. 60. Weinbroum AA: A single small dose of postoperative ketamine pro- 35. Lingford-Hughes A, Nutt D: Neurobiology of addiction and implica- vides rapid and sustained improvement in morphine analgesia in the tions for treatment. Br J Psychiatry 2003;182:97–100. presence of morphine-resistant pain. Anesth Analg 2003;96:789–795. 36. 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25 Postoperative Pain Management in the Ambulatory Setting NAVPARKASH SANDHU • SHYAMALA KARUVANNUR • DOMINIC HARMON Owing to advances in anesthetic and surgical techniques Patients should be familiar with the concept of pain and efforts to minimize costs, a growing number of surgical assessment and the need to assess pain on a regular basis in procedures are performed on an ambulatory (outpatient) order to modify analgesic treatment. They should be told basis.1 As of 2003, 70% of surgical procedures in North about the choices for postoperative pain management, and America were performed on an ambulatory basis.2 Though they should discuss these options with their doctors. The the majority of patients remain free of moderate to severe stepladder pattern of choosing analgesics should be explained pain, 5% to 33% of patients may suffer considerable postop- to patients (Fig. 25–1). Patients should be told to take oral erative pain.3,4 Pain is the most common cause of hospital analgesics “around the clock” rather than as needed. Patients admission or a visit to the emergency room after discharge.1,5 should have information about how to troubleshoot prob- lems with home-based analgesia11—for example, how to Ambulatory surgery is set to expand.6 It has already stop a home infusion device if they observe signs of toxicity expanded not only in terms of increasing complexity but or pump malfunction. also in terms of the selection of patients who are older and experiencing chronic illnesses such as diabetes and angina. Patients should be given contact information for further Persistent pain after discharge following ambulatory surgery advice after discharge. Physicians specializing in pain man- has numerous adverse effects. It is particularly harmful in agement should have access to a file, preferably computer- older adults with underlying chronic conditions.7 In this ized, with information on all ambulatory patients receiving chapter, the evidence-based options for ambulatory pain home pump infusions, with special reference to flow rates of management are reviewed to enable healthcare professionals local anesthetic, other therapies prescribed, and any changes to make appropriate analgesia choices for their patients. in therapy made by phone. This file will assure the patient that advice is available at all times in case of difficulty. Principles of Postoperative Pain Patients receiving continuous nerve blocks should be mon- Management in the Ambulatory Setting itored by phone every day that the infusion is continued and for a day after removal of the catheter. PATIENT EDUCATION MULTIMODAL THERAPY Patient education has been shown to decrease anxiety and postoperative pain.8,9 All instructions should be given both Kehlet et al12 have proposed that “total or optimal pain relief verbally and in written format. Patients should be informed allowing normal function cannot be achieved by a single drug about the likely duration of postoperative pain. This knowl- or method without major strain on equipment or surveil- edge helps patients understand the limited duration of acute lance system or without significant side-effects.” Multimodal pain and prepares them psychologically to deal with it. It is analgesia, also known as “balanced analgesia,” is a combina- important to note, however, that there is a disparity in reported tion of acetaminophen, nonsteroidal anti-inflammatory drugs pain levels after ambulatory surgery.10 The literature is incon- (NSAIDs), opioids, and local anesthetics. It is an attempt to sistent, because measures of postoperative pain have not been maximize analgesia through additive or synergistic effects systematically studied and reported in relation to specific of drugs and to minimize side effects through reduction in operations.10 A unified ambulatory surgery pain measurement dosage and the differences in side effect profiles. Multimodal strategy should be established so that patients can be informed analgesia is particularly relevant for ambulatory surgery.12 about the intensity of pain they are likely to experience after Specific treatment combinations are chosen according to the specific procedures. type of surgery, patient medical and psychological character- istics, and the availability of home support. One of the goals 249

250 SECTION IV • Postoperative Pain Management in Specific Clinical Settings Hospitalization for IV-PCA postoperative nausea and vomiting (PONV) and moderate to severe pain, which may delay discharge.19 New drugs and No relief drug combinations, new needle and catheter designs, and introduction of imaging techniques have improved the qual- Opioids ity and safety of regional anesthesia. Liposomal bupivacaine has been used in human volunteers in preliminary studies to nLeorcvaelANaonnoraeplrgsleeethlxsiNeeuictofsiscbsralenofoldcirekNsfSAIDS prolong anesthesia up to 48 hours after intradermal injec- tion.20,21 Wider application of such agents will provide pro- Figure 25-1 The successive steps in pharmacological choices for longed analgesia after single-shot injections and will ambulatory patients. IV-PCA, intravenous patient-controlled analgesia. revolutionize pain control in ambulatory patients. of multimodal analgesia is to reduce the use of opioids during A controversial issue in ambulatory surgery is whether and after ambulatory surgery to prevent undesirable side regional anesthesia offers significant advantages over general effects such as sedation, confusion, nausea, and vomiting. anesthesia. Published data are conflicting.22 All general and regional anesthetic techniques have advantages and disadvan- PREEMPTIVE ANALGESIA tages (Boxes 25–1 and 25–2). Acceptance of the technique by the surgeon and patient and the expertise of the anesthe- Preemptive analgesia is an antinociceptive treatment that pre- siologist are paramount. It is essential that each unit audit its vents establishment of altered processing of afferent input, own complication rates, recovery room times, and patient which amplifies postoperative pain.13 Overwhelming evi- opinions to determine outcome. dence from experimental studies shows the benefits of pre- emptive analgesia.14 However, the results of clinical studies Regional anesthetic techniques include subcutaneous infil- are controversial.15 Difficulties in clinical studies have been tration, intracavity and intra-articular instillation, field block, associated with the different definitions of preemptive anal- single peripheral nerve block, and plexus and neuraxial gesia used.13 Preemptive analgesia should prevent the estab- blocks. Regional anesthesia may be used as the sole anesthetic lishment of central sensitization caused by incisional and technique or in combination with general anesthesia to pro- inflammatory injuries during the period of surgery and the vide intraoperative and postoperative analgesia. Peripheral initial postoperative period.13 Local anesthetics block pain nerve blocks provide excellent analgesia with minimal adverse impulses traveling to the central nervous system and decrease effects. The preoperative analgesia can be extended post- postoperative analgesic requirements.16,17 To be effective in operatively through the use of peripheral nerve catheters. the immediate postoperative period, oral or rectal NSAIDs Neuraxial techniques are also an alternative to general anes- should be started before surgery. thesia. Disadvantages include the time to perform and await onset of block and potential, though rare, neurological com- PROTOCOL-BASED ANALGESIC MANAGEMENT plications. Other regional anesthetic techniques appropriate for ambulatory surgery are peribulbar, retrobulbar, and top- Protocol-based analgesic management can be a useful tool to ical anesthetics for ocular surgery, and intravenous regional standardize pain management strategies (Fig. 25–2). Use of anesthesia. protocols improves postoperative pain management.18 Continuous peripheral infusion techniques allow the rate GENERAL AND REGIONAL ANESTHETIC of administration to be titrated and facilitate adjustment of TECHNIQUES drug concentrations and combinations. The use of patient- controlled regional anesthesia at home is a major advance in The choice of anesthetic techniques depends on patient and this field. surgical factors. Major advances in ambulatory anesthetic techniques include the use of anesthetic agents of short dura- Several devices are used for ambulatory continuous tion and the growing use of regional anesthesia. The main nerve blocks. Disposable pressure release devices deliver local disadvantage of general anesthesia is the high incidence of anesthetic at a preset rate. They are more expensive than programmable pumps but avoid the problem of retrieving programmable pumps sent home with patients. The Accufuser (McKinley Medical, Wheat Ridge, Colo) can deliver at fixed rates of 0.5, 1, 2, 4, 5, 8 and 10 mL/hr and give bolus doses of 0.5, 1 and 2 mL with lockout intervals of 15, 30 and 60 minutes. It is a simple mechanical device with a large reservoir that can last for 2 to 3 days (Fig. 25–3). Programmable infusion pumps, such as the Gemstar Yellow (Hospira Inc., Lake Forrest, Ill) (Fig. 25–4), and PainPump2 (Stryker, Kalamazoo, Mich), are used with containers or larger bags containing local anesthetic for 2 to 3 days. These have the advantage of offering more choices for delivery rate and allow patient-controlled boluses as well. ACETAMINOPHEN Inexpensive and effective for mild pain, acetaminophen is well tolerated. It has multiple mechanisms of action.23

25 • Postoperative Pain Management in the Ambulatory Setting 251 Continuous nerve No nerve block Single-shot block nerve block No relief Analgesic or NSAID ± narcotic Increase infusion No relief to maximal rate Bolus of 10–15 mL of local anesthetic No relief Analgesic or Oral narcotic NSAID ± narcotic No relief of severe pain No relief Oral narcotic No relief of severe pain Admission IV-PCA Figure 25–2 Flow chart depicting management of pain in Catheter dislodged ambulatory patients. IV-PCA, intravenous patient-controlled Repeat nerve block or IV-PCA analgesia; NSAID, nonsteroidal anti-inflammatory drug. BOX 25–1 ADVANTAGES OF REGIONAL ANESTHESIA TECHNIQUES BOX 25–2 DISADVANTAGES OF REGIONAL ANESTHESIA ADVANTAGES TO PATIENT TECHNIQUES • Avoidance of general anesthesia • Onset is more time dependent • Improved pain relief • Specific side effects • Decreased recovery time • Prolonged blockade may result in delayed discharge • Decreased nausea and vomiting • Surgeon cooperation required • Expertise dependent ADVANTAGES TO SURGEON • Should be avoided postoperatively in patients with bony • Rapid postoperative assessment possible fractures complicated by large soft tissue swelling, owing to the risk of a compartment syndrome with such injuries. ADVANTAGES TO HOSPITAL Pain, an early warning symptom of compartment syndrome, might be masked by regional anesthesia. • Rapid recovery and earlier discharge • Decreased postoperative nursing requirements • Fewer unplanned admissions

252 SECTION IV • Postoperative Pain Management in Specific Clinical Settings Figure 25–4 Gemstar Yellow (Hospira) is reusable, compact, and versatile—it can be programmed to deliver basal or bolus analgesia. 4 grams in adults in a 24-hour period. Acetaminophen is also used in combination with opioids for postoperative pain. The ceiling on the recommended dose of nonopioid limits the usefulness of combination drugs to the treatment of short-term mild to moderate pain (Table 25–1). Figure 25–3 Accufuser (elastomeric pump) requires no batteries NONSTEROIDAL ANTI-INFLAMMATORY DRUGS and has several choices of basal and bolus delivery through selection of tubes of varying diameter. Unless contraindicated, all patients with postoperative pain should receive an NSAID.25 The traditional NSAIDs, called Unlike NSAIDs, it does not irritate the gastric mucosa, affect nonselective NSAIDs, have significant gastrointestinal, hema- platelet function, or cause renal insufficiency. Acetaminophen tological, and renal adverse effects, which are mediated has significant opioid-sparing effects.24 The recommended through the inhibition of the isoenzyme cyclooxygenase-1 rectal dose (up to 45 mg/kg) is higher than the oral dose (Cox-1). These drugs help decrease opioid requirements. (15 mg/kg) because of unreliable absorption from the rectal Examples are aspirin, ibuprofen, naproxen, and diclofenac route. The maximum dose is 90 mg/kg in children and (see Table 25–1). Aspirin should be avoided in patients with a history of peptic ulcer disease and in children (risk of Reye’s syndrome). These drugs can be used alone or in combination TABLE 25–1 Analgesics and NSAIDs Drug Dose and Route in Adults Dose and Route in Children Comments Acetaminophen 500–1000 mg every 30–40 mg/kg loading dose; Toxic doses can cause hepatic toxicity Aspirin 3–4 hr PO 10–15 mg/kg every 4–6 hr PO/PR Ibuprofen Adult maximal dose Maximal dose in children Total 75 mg/kg/day in children Associated with Reye’s syndrome Ketorolac 4000 mg/day 90 mg/kg/day Gastric irritation Naproxen 325–650 mg every 4–6 hr PO 12–20 mg/kg every 4–6 hr PO Gastric irritation, rarely 200–800 mg every 6–8 hr PO 4–10 mg/kg every 6–8 hr PO thrombocytopenia, skin rashes, headache, dizziness, blurred vision, Loading dose 30 mg IM/IV; 0.5 mg/kg every 6–8 hr PO or IM and toxic amblyopia 10 mg every 4–6 hr PO Use not to exceed 5 days 5 mg/kg every 12 hr PO Somnolence, dizziness, headache, 250–500 mg every 12 hr PO gastrointestinal pain, dyspepsia Nausea, vomiting, gastric bleeding, drowsiness, dizziness, dermatological lesions, blood dyscrasias IM, intramuscular; IV, intravenous; PO, orally; PR, per rectum.

25 • Postoperative Pain Management in the Ambulatory Setting 253 TABLE 25–2 Dose Recommendations and Duration of Action of Cyclooxygenase (Cox-2) Inhibitors Drug Dose and Route in Adults Duration (hr) Cox-2/Cox-1 Activity Celecoxib 100–400 mg every 12 hr PO 4–8 8 Etoricoxib 60–240 mg PO >24 106 Parecoxib 20 mg IM/IV 6–12 Rofecoxib 25–50 mg PO 12–24 — Valdecoxib 20 mg PO 6–12 35 30 IM, intramuscular; IV, intravenous; PO, oral. with opioids or nerve blocks. The choice of NSAID is based NONPHARMACOLOGICAL TECHNIQUES on the patient’s medical condition. Nonpharmacological techniques can be used in the treatment Cox-2–selective NSAIDs appear to be as effective as non- of pain in the ambulatory setting.32 The clinical efficacy of selective NSAIDs in suppressing inflammation and providing electroanalgesia techniques remains controversial owing to analgesia for ambulatory surgery26 with less risk of gastrointesti- potential sources of bias and difficulty in quantifying the nal toxicity. Another significant advantage of the Cox-2– inherent placebo effect of the therapy. Other nonpharmaco- selective NSAIDs is that they do not impair platelet function logical techniques that have been used as analgesic adjuvants in the perioperative period.27 Parecoxib is a long-acting in the perioperative period are cryoanalgesia, ultrasound, injectable formulation that is effective in ambulatory surgery and hypnosis.33,34 Randomized clinical studies are required (Table 25–2).28 Rofecoxib has been withdrawn by the manu- to establish effects of these modalities on analgesic outcome facturer, and a warning has been added to the use of celecoxib after ambulatory surgery. and valdecoxib owing to the potential association of their long- term use with an increased incidence of myocardial infarction. Specific Procedures OPIOIDS ABDOMINAL SURGERY Usually a short-acting opioid, such as fentanyl, is started Inguinal Hernia Repair intraoperatively to supplement general anesthesia. In the post- anesthesia recovery unit, intravenous fentanyl or morphine The ilioinguinal nerve can be blocked by a “double-pop” can be used for moderate to severe pain. After ambulatory technique, in which 10 mL of local anesthetic is injected surgery discharge, morphine is associated with more side 2.5 cm superomedial to the anterior superior iliac spine. effects than is fentanyl.29 A long-acting oral opioid should be Even if neuraxial or general anesthesia is used, local anes- considered for surgery that is likely to result in moderate thetic should be injected along the surgical incision. to severe postoperative pain after discharge.30 Oral opioids Alternatively, surgeons can inject 5 to 10 mL of 0.25% bupi- commonly used in the postoperative period are listed in vacaine after exposure or at the end of surgery along the Table 25–3. Controlled-release oxycodone has a better side- incision. NSAIDs and/or opioids should be given routinely effect profile than controlled-release morphine after ambu- before anesthesia ends. Pain can be decreased by having latory surgery discharge.31 Adverse effects of opioids include the patient press the wound with the palms during cough- constipation, nausea, vomiting, sedation, and respiratory ing or movement. Paravertebral block, which has been used depression. Patients should be given appropriate advice on for pain control, offers pain relief similar to that achieved how to manage these side effects. TABLE 25–3 Postoperative Oral Opioids Drug Dose and Route in Adults Dose and Route in Children Comments Morphine 10–20 mg every 2–3 hr 0.3 mg/kg every 3–4 hr Cautious use in asthmatics Codeine 15–60 mg every 4–6 hr 1 mg/kg every 3–4 hr Can cause respiratory depression in infants Useful for moderate to severe pain Morphine SR 15–30 mg every 6–8 hr — Can be combined with acetaminophen Meperidine 50–150 mg every 3–4 hr — Contraindicated with monoamine oxidase inhibitors Hydromorphone 2–4 mg every 4–6 hr 0.06 mg/kg every 3–4 hr Oxycodone 5–10 mg every 3–4 hr 0.2 mg/kg every 3–4 hr Oxycodone SR 10–20 mg every 12 hr — SR, slow release.

254 SECTION IV • Postoperative Pain Management in Specific Clinical Settings by ilioinguinal nerve block and infiltration of the surgical auricular nerve, a branch of the superficial cervical plexus.38 incision.35 Two milliliters of 0.25% bupivacaine with epinephrine 1:200,000 is injected subcutaneously at the midpoint of the Appendectomy posterior border of the sternocleidomastoid muscle. In addi- tion, NSAIDs and opioids should be used. Patients who undergo uncomplicated interval appendectomy can be sent home the day of surgery. The surgical wound GYNECOLOGICAL SURGERY should be injected with 5 to 10 mL of bupivacaine 0.25%. NSAIDs and opioids are used in the early postoperative Surgical incisions can be infiltrated with 0.25% bupivacaine period. (maximum 2 mg/kg) at the end of gynecological surgery. NSAIDs and opioids should be prescribed. For uterine Laparoscopic Cholecystectomy cramps, NSAIDs are especially helpful.39 All incision sites used for laparoscopic cholecystectomy UPPER EXTREMITY SURGERY should be injected before incision with lidocaine 0.5% and after closure with 2 to 3 mL of bupivacaine 0.25%. An NSAID Shoulder Surgery should also be given before discharge. Acetaminophen/codeine combinations are given as soon as the patient can take oral Shoulder and elbow operations are followed by a 25% medications. Oral oxycodone may be used for patients with incidence of severe pain.4 poorly controlled pain. Interscalene Block. For operations around the shoulder, UROLOGICAL SURGERY an interscalene block can be used as the primary anesthetic technique or as an adjunct to general anesthesia. Single-shot Circumcision can be performed with the use of penile block interscalene blocks provide excellent analgesia for the alone in adults. In children and infants, general anesthesia immediate perioperative period but may be insufficient after is also employed. Dorsal penile block can be performed discharge from the hospital.40 Shoulder arthroscopy or rota- with the use of 0.1 to 0.2 mL/kg of 0.25% bupivacaine in tor cuff repair can be performed after interscalene block infants and children; it provides pain relief lasting 24 hours. using nerve stimulation, paresthesias, or ultrasound guid- Epinephrine should never be used because of risk of gangrene ance techniques. A catheter placed in the neck near roots/ owing to vasospasm. Local application of EMLA (eutectic trunks through the interscalene groove41 or through the par- mixture of lidocaine 2.5% and prilocaine 2.5%) cream gives avertebral or posterior approach42 facilitates postoperative equivalent pain relief although its duration of action is shorter pain control. than that of dorsal penile block.36 This measure can be easily repeated at home.36 NSAIDs should be prescribed routinely, Patients can be discharged home with disposable infusion and opioids may be added. devices (e.g., Accufuser [McKinley Medical] or PainPump [Stryker]) or reusable programmable pumps like Gemstar Before orchidectomy, orchiopexy, or hydrocele repair, Yellow (Hospira). Use of these devices should be coordinated the spermatic cord can be grasped between index finger with visiting home nurse services where feasible. These infu- and thumb through the scrotal skin, and a 23-gauge needle sions, however, may not reliably control pain.43 Patients may passed into the cord. Bupivacaine 0.25% or ropivacaine have to administer several boluses of local anesthetic to 0.2% (3–4 mL) can be injected after intravascular placement achieve control of pain.43 Complications include incidental of the needle has been ruled out. NSAIDs and opioids are also nerve blocks; phrenic nerve block, recurrent laryngeal nerve given. Scrotal skin should be injected with lidocaine prior to block, and stellate ganglion block should be explained to incision. Alternatively, the surgeon can inject 4 to 5 mL of the patient. 0.25% bupivacaine into the spermatic cord after exposing it. Supporting the testicles in a bandage or a scrotal support Suprascapular Nerve Block. Suprascapular nerve blocks decreases postoperative pain. Alternatively, the ilioinguinal can be achieved by injection of 10 mL of a longer-acting agent nerve is blocked near the anterior superior iliac spine. such as bupivacaine or levobupivacaine 0.25% or ropivacaine 0.2% superior to the midpoint of the spine of the scapula. PLASTIC SURGERY Although less effective than an interscalene block, supra- scapular nerve block offers an alternative in patients with Plastic surgery of the breast and abdomen can be followed severe pulmonary disease, in whom phrenic nerve blockade by severe postoperative pain. Psychological overlay in patients may compromise respiration. The supraclavicular nerve block undergoing these procedures may increase pain. They should offers sufficient pain relief postoperatively.44 receive NSAIDs, opioids, and anxiolytics. Paravertebral blocks using bupivacaine 0.5% (0.3 mL/kg) or ropivacaine can Surgery Distal to the Midpoint of the Arm relieve postoperative breast pain for many hours.37 Infraclavicular Catheter. Infraclavicular brachial plexus EAR, NOSE, AND THROAT PROCEDURES catheter techniques avoid undesirable incidental blockade of the phrenic, recurrent laryngeal, or stellate ganglion In children undergoing tympanomastoid surgery, pain can nerves. Catheters here are more secure, and pericatheter be decreased on the day of surgery by a block of the great leaks are uncommon. Pneumothorax is unlikely.

25 • Postoperative Pain Management in the Ambulatory Setting 255 With the nerve stimulator technique, a vertical approach Figure 25–6 Open reduction and internal fixation of the radius is commonly used. An 18-gauge insulated Touhy needle fracture of the right arm and repair of multiple lacerations of the left arm (Contiplex, B. Braun Medical, Bethlehem, Pa) is inserted were performed simultaneously with the use of bilateral infraclavicular beneath the coracoid process. After muscular twitches are blocks using ultrasound in this 14-year-old male patient. A right-side obtained in the hand or forearm with a current of 0.3 to catheter was used for postoperative analgesia. 0.4 mA, a 20-gauge catheter is threaded through the needle. A Stimulating catheter (Arrow International, Reading, Pa) of the artery, the catheter position is satisfactory. If it moves allows stimulation of the plexus, and the position of its tip toward the vein, the catheter should be withdrawn and the is confirmed before injection. If there is no response, the air test repeated. When in proper position, the catheter is catheter may be manipulated to optimize the muscle twitch. fixed with a transparent dressing. With this technique, the Stimulating catheters have a limited role in the outpatient catheter is unlikely to dislodge or leak because its path curves setting. several times. In the ultrasound-guided technique, the axillary vessels Axillary Catheter. An axillary catheter can be used for and brachial plexus are imaged below the clavicle in the area analgesia after operations of the hand, wrist, or elbow. The of the coracoid process of the scapula.45 When the cords are catheter entry site is through a moist area in the axilla, making best visualized, the transducer’s position is labeled with a these catheters more prone to infection. The needle can be skin marker. The region is prepared with antiseptic solution introduced by a loss-of-resistance technique, or its location can and sterile drapes. A sterile cover containing conducting be confirmed with electrical stimulation before the catheter gel is put on the ultrasound transducer. A 17-gauge Touhy is placed. Pericatheter leaks and dislodgments are more needle is introduced 1 to 2 cm cephalic to the transducer. common with axillary than with infraclavicular catheters. The needle is directed between the axillary artery and vein, Infusions at rates of 4 to 6 mL/hr of bupivacaine 0.25% or and local anesthetic is deposited around the medial brachial ropivacaine 0.2% are used; addition of patient-controlled plexus cord. The needle is withdrawn into the pectoralis boluses improves patient satisfaction.46 minor muscle and redirected between the axillary artery and lateral cord. After needle position is confirmed, local anesthetic is injected. The needle is then advanced a little deeper and, without release of pressure, the needle direction is changed to a more horizontal orientation and advanced between the posterior cord and the axillary artery. The third injection is delivered at this location, and a 20-gauge epidural catheter (Flextip [Arrow International]) is inserted. The catheter position is now confirmed, and the catheter is withdrawn under imaging to bring the tip posterior to the axillary artery (Figs. 25–5 and 25–6). The catheter curls between the posterior and medial cords, and its position is better appreciated on withdrawal. Because the tip may be difficult to identify, 1 to 2 mL of air is injected through the catheter, and the point from which the air exits (usually hyperechoic or white) is seen. If the air spreads on both sides Figure 25–5 Ultrasonographic image of the cords of the brachial LOWER EXTREMITY OPERATIONS plexus and the catheter. L, M, and P label lateral, medial, and poste- rior cords, respectively. The catheter is marked by white arrows. Knee Arthroscopy AxA, axillary artery; AxV, axillary vein; PMa, pectoralis major muscle; PMi, pectoralis minor muscle. Knee arthroscopy is the most common ambulatory orthopedic procedure of the lower extremity. It can be performed with the use of femoral and sciatic blocks. When performed with central neuraxial block or general anesthesia, a continuous femoral nerve block is useful for control of postoperative pain. There are several other ways of supplying postopera- tive analgesia. A femoral nerve block (Figs. 25–7 and 25–8)

256 SECTION IV • Postoperative Pain Management in Specific Clinical Settings Figure 25–7 Bilateral femoral catheters provide postoperative Figure 25–9 In a patient undergoing hip surgery, an epidural analgesia for bilateral knee surgery. catheter was placed at the L2–L3 level, and a psoas compartment catheter was placed at the L4 level via the nerve stimulator technique. or its variant, the fascia iliac block, gives better pain relief than intra-articular infusions.47 A Contiplex or a Stimulating Foot and Ankle Surgery catheter may be placed via a nerve stimulator or ultrasound- guided technique (see earlier). NSAIDs in combination with The sciatic nerve or its terminal branches can be blocked an oral opioid may be added if the local anesthetic does not with either a single-injection or continuous-catheter tech- give adequate pain relief. The patient should be informed nique. Use of this nerve block decreases the requirement for that there may be weakness of the quadriceps muscle and NSAIDs and opioids postoperatively.49 The catheter should should use caution when trying to ambulate. The psoas be inserted through the lateral hamstrings in order to secure compartment block and catheter techniques (Fig. 25–9) are it (Figs. 25–10 and 25–11). alternatives that offer similar analgesia to that given by femoral catheters inserted below the inguinal ligament.48 Summary Bupivacaine solutions can be injected into the intra-articular space as a single injection or via a continuous catheter tech- Successful ambulatory surgery depends on analgesia that nique. Analgesia is less satisfactory than that provided by a is effective, has minimal adverse effects, and can be safely femoral nerve block.21 managed by the patient at home after discharge. A number of studies have established that the provision of effective postoperative analgesia is inadequate for a significant pro- portion of patients. Preemptive analgesia should be given to all patients unless there are specific contraindications. Figure 25–8 Radiograph of the patient shown in Fig. 25–7. The Figure 25–10 Popliteal fossa catheter placed for surgery and catheter on the right side was directed high up in the psoas compart- postoperative analgesia. ment, and local anesthetic mixed with radiopaque contrast is spreading along the psoas muscle. The left catheter was placed posterior to the femoral nerve, below the inguinal ligament. The local anesthetic with radiopaque contrast is seen descending toward an unintended loca- tion. The two sides had equally satisfactory analgesia with continuous infusions.

25 • Postoperative Pain Management in the Ambulatory Setting 257 Figure 25–11 Ultrasonographic image of popliteal fossa catheter 18. Chung F, McGrath B: Postoperative pain following discharge after and sciatic nerve of the patient shown in Fig. 25–10, with approach ambulatory surgery. Can we do better? [abstract A20]. Can J Anaesth using ultrasonography. White arrows mark the catheter lying anterior 2003;50:20A. to the sciatic nerve. 19. Rocchi A, Chung F, Forte L: Canadian survey of postsurgical pain and A standardized multimodal postdischarge analgesic regimen pain medication experiences. Can J Anaesth 2002;49:1053–1056. tailored to each patient’s expected postoperative pain levels should be prescribed. Patient follow-up by telephone ques- 20. Grant GJ, Barenholz Y, Bolotin E, et al: A novel liposomal bupivacaine tionnaire confirms whether surgical procedures result in formulation to produce ultralong-acting analgesia. 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Acute Pain Management Guideline Panel: Acute Pain Management: Operative or Medical Procedures and Trauma. (Clinical Practice Guideline 4. Chung F, Ritchie E, Su J: Postoperative pain in ambulatory surgery. AHCPR Publication No. 92-0032.) Rockville, Md, Agency for Health Anesth Analg 1997;85:808–816. Care Policy and Research, 1992. 26. Karasch ED: Perioperative COX-2 inhibitors: Knowledge and challenges. 5. Mitchell M: Pain management in day-case surgery. Nurs Stand 2004; Anesth Analg 2004;98:1–3. 18:33–38. 27. Silverman D, Halaszynski T, Sinatra R, et al: Rofecoxib does not compromise platelet aggregation during anesthesia and surgery. Can J 6. Coll AM, Ameen JR, Moseley LG: Reported pain after day surgery: a Anaesth 2003;50:1004–1008. critical literature review. J Adv Nurs 2004;46:53–65. 28. Barden J, Edwards J, McQuay H, et al: Oral valdecoxib and injected parecoxib for acute postoperative pain: A quantitative systematic 7. McCaffery M, Pasero C: Pain: Clinical Manual, 2nd ed. St. Louis, review. BMC Anesthesiol 2003;3:1–8. Mosby, 1999. 29. Claxton AR, McGuire G, Chung F, et al: Evaluation of morphine versus fentanyl for postoperative analgesia after ambulatory surgical procedures. 8. Hekmat N, Burke M, Howell SJ: Preventive pain management in the Anesth Analg 1997;84:509–514. postoperative hand surgery patient. Orthop Nurs 1994;13:3. 30. Sunshine A, Olson NZ, Rivera J: Analgesic efficacy of controlled- release oxycodone in postoperative pain. J Clin Pharmacol 1996;26: 9. Goldsmith DM, Safran C: Using Web to reduce pain following 595–603. ambulatory surgery. Proc AMIA Symp 1999;780–784. 31. Mucci-Lorusso P, Berman B, Silberstein P, et al: Controlled-release oxycodone compared with controlled-release morphine in the treatment 10. Coll AM, Ameen JRM, Moseley LG: Reported pain after day surgery: of cancer pain: A randomized, double-blinded, parallel-group study. A critical literature review. J Adv Nursing 2004;46:53–65. Eur J Pain 1998;2:239–249. 32. White PF: The role of non-opioid analgesic techniques in the manage- 11. Marquardt HM, Razia PA: Pre-packed take home analgesia for day case ment of pain after ambulatory surgery. Anesth Analg 2002;94: surgery. Br J Nurs 1996;5:1114–1118. 577–585. 33. Hashish I, Hai HK, Harvey W, et al: Reduction of postoperative pain 12. Kehlet H, Dahl J: The value of “multimodal” or “balanced analgesia” in and swelling by ultrasound treatment: a placebo effect. Pain 1988;33: postoperative pain treatment. Anesth Analg 1993;77:1048–1056. 303–311. 34. Gam AN, Thorsen H, Lonnberg F: The effect of low-level laser 13. Kissin I: Preemptive analgesia. Anesthesiology 2000;93:1138–1143. therapy on musculoskeletal pain: A meta-analysis. Pain 1993;52: 14. Woolf CJ: Evidence of a central component of post-injury pain 63–66. 35. Klein SM, Pietrobon R, Nielsen KC, et al: Paravertebral somatic nerve hypersensitivity. Nature 1983;308:686–688. block compared with peripheral nerve blocks for outpatient inguinal 15. Moiniche S, Kehelet H, Dahl JB: A qualitative and quantitative system- herniorrhaphy. Reg Anesth Pain Med 2002;27:476–480. 36. Choi WY, Irwin MG, Hui TWC, et al: EMLA cream versus dorsal atic review of preemptive analgesia for postoperative relief: The role of penile nerve block for post circumcision analgesia. Anesth Analg 2003; timing of analgesia. Anesthesiology 2002;96:725–741. 96:396–399. 16. Honama T, Imaizumi T, Chiba M, Niwa J: Preemptive analgesia for 37. Kairaluoma PM, Bachmann MS, Korpinen AK, et al: Single-injection postoperative pain. Neurol Surg 2002;30:171–174. paravertebral block before general anesthesia enhances analgesia after 17. Nguyn A, Girard F, Boudreault D, et al: Scalp nerve blocks decrease breast cancer surgery with and without associated lymph node biopsy. the severity of pain after craniotomy. Anesth Analg 2001;93: Anesth Analg 2004;99:1837–1843. 1272–1276. 38. Suresh S, Barcelona S, Young N, et al: Postoperative pain relief in chil- dren undergoing tympanomastoid surgery: Is regional block better than opioids? Anesth Analg 2002;94:859–862. 39. Huang YC, Tsai SK, Huang CH, et al: Intravenous tenoxicam reduces uterine cramps after Cesarean delivery. Can J Anaesth 2002;49: 384–387. 40. Wilson AT, Nicholson E, Burton L, Wild C: Analgesia for day-case shoulder surgery. Br J Anaesth 2004;92:414–415. 41. Klein SM, Grant SA, Greengrass RA, et al: Interscalene brachial plexus block with a continuous catheter insertion system and a disposable infusion pump. Anesth Analg 2000;91:1473–1478. 42. Borene SC, Rosenquist RW, Koorn R, et al: An indication for continuous cervical paravertebral block (posterior approach to the interscalene space). Anesth Analg 2003;97:898–900. 43. Singelyn FJ, Seguy S, Gouverneur JM: Interscalene brachial plexus block after open shoulder surgery: Continuous vs patient controlled infusion. Anesth Analg 1999;89:1216–1220.

258 SECTION IV • Postoperative Pain Management in Specific Clinical Settings 44. Singlyn FJ, Lhotel L, Fabre B: Pain relief after arthroscopic shoulder 47. Iskander H, Benard A, Ruel-raymond J, et al: Femoral blocks provide surgery, a comparison of intraarticular analgesia, suprascapular nerve superior analgesia compared with intra-articular ropivacaine after anterior block and interscalene block. Anesth Analg 2004;99:589–592. cruciate ligament repair. Reg Anesth Pain Med 2003;28:29–32. 45. Sandhu NS, Capan LM: Ultrasound guided infraclavicular brachial 48. Kaloul I, Guay J, Cote C, Fallaha M: The posterior lumbar plexus plexus block. Br J Anaesth 2002;89:254–259. (psoas compartment) block provides similar postoperative analgesia after total knee replacement Can J Anaesth 2004;51:45–51. 46. Iskander H, Rakotondriamihary S, Dixmerias F, et al: Analgesia with continuous axillary block after severe hand trauma: Self-administration 49. Mendicino RW, Statler TK, Catanzariti AR: Popliteal sciatic nerve blocks vs continuous infusion. Annales Francaises d’Anesthésie et de after foot and ankle surgery: An adjunct to postoperative analgesia. Réanimation. 1998;17:1099–1103. J Foot Ankle Surg 2002;41:38–41.

26 Can We Prevent Chronic Pain after Surgery? WILLIAM A. MACRAE Epidemiological studies of patients attending pain clinics in Mechanisms of Chronic Pain the 1990s showed that surgery and trauma are major causes after Surgery of chronic pain.1,2 This finding led to publications on the general subject of chronic pain after surgery.3–5 Until then, Any operation has the potential to cause chronic pain. There chronic pain after surgery had been a neglected topic, are many different mechanisms, but changes in the nervous although pain after individual operations had been docu- system are the most important factor. mented. The literature was fragmented and dispersed, so no overall picture was possible. This chapter does not go over Neuropathic pain is complex, with many etiologies and this ground again, but discusses mechanisms, investigates mechanisms.14 Obviously, nerve injury such as transection, what is known about risk factors, and points to possibilities stretching, or constriction causes changes. However, it is for prevention. Those who wish to read about the general important to appreciate that the pain system responds to topic of chronic pain after surgery are referred to the refer- injury to other tissues as well.15 One example that has been ences cited in this paragraph. investigated extensively is thermal injury to the skin, such as sunburn. In the past, the pain after sunburn was explained as Chronic pain after surgery has many forms and presenta- being caused by “damage to the skin.” This is an inadequate tions. Several different types of pain may occur after the explanation, as one would not expect injury to increase sen- same operation, and there are many mechanisms. In open sitivity in a sensory system; for example, an eye injury would thoracotomy, for example, in order to gain access to the chest, not improve visual acuity. Thermal injury to the skin causes the surgeon has to either resect a piece of rib or spread the a cascade of changes; for example, inflammatory mediators ribs. Either maneuver inevitably produces skeletal trauma to are released from the damaged cells, which bathe the nerve the ribs or to the joints at the posterior and anterior articu- endings of the C and Aδ fibers. This changes the nociceptors lations. The intercostal nerves lie just deep to the inferior by reducing their thresholds and increasing excitability. The border of the ribs and are vulnerable to injury, which can hyperexcitability occurs both at the periphery and in the cause neuropathic pain. The lungs or other viscera will also spinal cord. The result is that previously innocuous stimuli be affected by the operation and hence may contribute to are painful (allodynia), and more pain than usual is experi- the pain. Chest drains are often a source of pain.6 After breast enced from painful stimuli (hyperalgesia). It is this sensitiza- surgery, patients report many unpleasant symptoms, such as tion of the sensory nerves to the skin (caused by the damage) numbness, tingling, swelling, and sensitivity, which may that causes the pain. In the same way that thermal injury cause as much distress as pain.7,8 The pain may be phantom causes sensitization, the inevitable injuries involved in sur- pain,9 neuropathic pain caused by damage to the intercosto- gery can also cause changes, resulting in sensitization and brachial nerve,10 or scar pain.11 It is clear, then, that even for hyperalgesia. a given operation, there is no one postsurgical pain syn- drome, but rather a diverse group of problems. Injury changes the nervous system not only at the periph- ery and the spinal cord but also at the brain. Remapping of It should also be obvious that these pain syndromes are the sensory cortex after deafferentation was first described not unique to postoperative states, but are similar to prob- in 1991.16 This phenomenon has been widely described in lems seen with other etiologies. The treatments are therefore humans after limb amputation.17 It can occur soon after not unique either; a neuropathic pain syndrome after surgery injury18 and has been shown to change with time.19 Plasticity should be treated in the same way as any other neuropathic also occurs in the thalamus.20 Paradoxically, injury to the brain pain, be it diabetic neuropathy, traumatic, or post-herpetic can cause misperceptions at the periphery, such as the case neuralgia.12 A postoperative mechanical musculoskeletal pain described by Halligan et al,21 in which a patient experienced should be treated in the same way as other musculoskeletal the sensation of having a third arm after a stroke. problems.13 259

260 SECTION IV • Postoperative Pain Management in Specific Clinical Settings Many different sorts of injury cause sensitization of the DEMOGRAPHIC AND PSYCHOSOCIAL FACTORS nervous system, both peripheral and central. This hypersen- sitivity may confer an evolutionary benefit by preventing an The influence of age has been reported in two studies of pain injured animal from further damaging itself, encouraging rest, after breast surgery. Tasmuth et al27 reported that younger and allowing healing. The sensitivity should return to normal patients have more pain postoperatively and over the long after the injury has healed, but it does not always do so. Failure term as well as bigger tumors. Smith et al28 found the inci- to return to normal from this injury-induced hyperalgesic dence of chronic pain after mastectomy to be 26% in patients state is probably one of the main causes of chronic pain after older than 70 years, 40% in those 50 to 69 years, and 65% surgery. Why the system fails to adjust in this way is unknown. in those 30 to 49 years. This study also showed that several Animal work suggests that there is a genetic component to other demographic factors related to age may be influential, the development of neuropathic pain.22,23 such as marital status, housing, and employment. Understanding the scale of the changes to the nervous Age does not seem to be a risk factor for phantom pain system and the mechanisms that predispose to chronic pain after upper or lower limb amputation.29–31 Demographic fac- after surgery is important for many reasons. Such an under- tors do not seem to be important in pain after thoracotomy.6,32 standing can change the climate of blame that develops when patients have pain after an operation. It is not possible to Many studies have shown that pain is an important cause perform surgery without some damage to tissues; a hyperal- of disability.33 Those who attribute their pain to a specific gesic state is induced after any operation, regardless of how trauma (for example, an operation) report significantly higher it is done. Normally this state reverts to normal as healing levels of emotional distress, life interference, and pain severity occurs, but not always. Whether a patient experiences chronic than those whose pain had an insidious or spontaneous pain after surgery is therefore more likely to depend on the onset, regardless of the extent of objective physical findings.34 “set” of the patient’s nervous system than on precisely what This finding raises the possibility that by preparing patients the surgeon did. When patients have chronic pain after sur- better—for example, giving information about chronic gery it is inappropriate to assume that the surgeon has nec- pain before obtaining consent to surgery—we can change essarily done anything wrong or to lay blame. It should also patients’ perceptions, leading to better outcomes.35 be clear that acting on simplistic notions about treatment, such as by performing simple nerve blocks or further surgery, PREOPERATIVE PAIN is unlikely to help and may well do harm by causing further damage. The extent of the changes in the nervous system In a careful study of the influence of preamputation pain on suggests that pharmacological, psychological, and behav- postamputation stump and phantom pain, Nikolajsen et al36 ioral therapies may be more beneficial to patients than inva- showed that preamputation pain significantly raised the sive treatments. incidence of stump and phantom pain postoperatively and of phantom pain at 3 months. However, patients overesti- Risk Factors mated the severity of their preamputation pain 6 months after undergoing amputation (compared with their pream- Most surgery is performed because the patient has a disease putation scores), and although patients stated that their or injury that is amenable to improvement by surgery. In phantom pain had been similar to their preamputation pain, other cases, patients have cosmetic plastic surgery and sur- these statements were not borne out by the patients’ actual gery for social reasons, such as female sterilization and vasec- descriptions before and after amputation. tomy. Also, some patients have inappropriate surgery. Many patients continue to have surgery for back pain despite evi- In a study of women undergoing mastectomy for breast dence that in many cases it is unhelpful and may in fact make cancer, Kroner et al9 found a correlation between premastec- the problem worse.24 Many patients with abdominal pain tomy breast pain and both phantom breast pain and non- have visceral hyperalgesic syndromes, and these problems, painful phantom breast sensations. too, may be made worse by surgery. Such patients can enter a vicious circle of repeated operations in the vain hope of In patients undergoing thoracotomy for cancer, 48% of cure or because of complications from previous operations. those who had been taking narcotics before thoracotomy went on to experience chronic post-thoracotomy pain, whereas only Risk factors for chronic pain after surgery must therefore 5% of those who had not been taking narcotics did so.37 start with risk factors for diseases that lead to surgery. To pre- Whether the postoperative pain was a continuation of the vent phantom pain and stump pain after limb amputation, preoperative pain or a true postsurgical pain syndrome is the single most important strategy would be to eliminate impossible to say. smoking and obesity, because peripheral vascular disease and diabetes are the two most common reasons for amputa- TYPE OF SURGERY tion.25 The risk factors for diseases such as breast cancer are complex, involving genetic, demographic, and lifestyle fac- The incidence of chronic pain after surgery varies according tors.26 Screening and early detection will influence outcome to the type of operation and how it is performed. For exam- in such diseases. These factors cannot be ignored if we are ple, Table 26–1 shows the incidences of chronic pain after to take a realistic and broad view of risk factors for chronic various types of breast surgery. pain after surgery. In a study from Finland,8 women undergoing surgery for breast cancer in high-volume surgical units suffered less chronic pain than those having operations in hospitals that had less experience in breast surgery.

26 • Can We Prevent Chronic Pain After Surgery? 261 TABLE 26–1 Incidence of Chronic Pain After Thompson45 showed that chemotherapy increased the risk Breast Surgery of phantom pain considerably (Table 26–2). Procedure Incidence (%) GENETIC FACTORS Breast reduction 22 Why only some people have chronic pain after surgery is an Mastectomy 31 interesting question. Clearly there are many factors deter- Breast augmentation mining individual susceptibility, and it seems likely that part 22 of the reason will be genetic. Research in mice shows that Silicone 33 there is a genetic influence in whether the animal suffers Saline 50 chronic pain after nerve injury.22,23 Diatchenko et al46 pub- Submuscular 21 lished the first paper demonstrating an association among Subglandular a genetic polymorphism, pain sensitivity, and the risk of Mastectomy and reconstruction 30 development of a chronic pain syndrome in humans. Some No implant 53 human pain syndromes have been shown to have a genetic Implant component, and the clinical suspicion of many researchers in this field is that some of these conditions may be markers Modified from Wallace MS, Wallace AM, Lee J, Dobke MK: Pain after for a greater likelihood of development of chronic pain after breast surgery: A survey of 282 women. Pain 1996;66:195–205. injury. These conditions include migrainous headaches, fibromyalgia syndrome, irritable bowel syndrome, bladder Whether the cause of breast surgery influences the incidence frequency and urgency, and Raynaud’s phenomenon (partic- of chronic pain is difficult to establish, because different ularly bipolar, with both excessively cold extremities in cold operations are performed for malignant and benign condi- weather and erythromelalgia [“burning-hot” feet], usually at tions, and the type of surgery does influence the incidence night). of pain.38 Against this possibility it must be said that many patients The evidence for the effect of surgical technique on pain have several operations but experience chronic pain only after thoracotomy is contradictory, with some papers showing after a particular one. Some patients who undergo bilateral a difference6 but others showing no long-term difference.39 operations have chronic postsurgical pain syndrome on one The level and type of amputation does not appear to influence side but not the other. This is clearly a complex but fascinat- the incidence of phantom pain.31 ing area that will probably provide as many interesting ques- tions as answers in the next few years. In a review of pain after hernia repair, Callesen and Kehlet40 reported that there was no difference between the PERIOPERATIVE PAIN various open techniques but that laparoscopic herniorrhaphy resulted in less pain and shorter convalescence than open The question of whether perioperative pain is a risk factor repair. For cholecystectomy, the incidence of long-term right for chronic pain has been the subject of many studies. It is upper quadrant pain was reported as 3.4% after laparoscopic of great importance, because perioperative pain is a factor cholecystectomy but 9.7% after open cholecystectomy.41 over which we have some control. Early studies were con- founded by the problem of patients’ memory of past pain, Two studies from Finland have shown that chronic pain a notoriously tricky subject. Studies have shown that is equally common after thoracotomy for malignant disease patients are not good at accurately rating past pain. The past and for benign disease.32,42 Another study, however, found pain report is influenced by many factors, including the that chronic pain was more common after surgery for benign amount of pain suffered subsequently, especially at the time esophageal disease than for lung cancer.6 TABLE 26–2 Phantom Pain in Pediatric Cause of amputation does not influence the incidence of Amputees phantom pain.31 Houghton et al43 showed no difference in the incidence of phantom pain between traumatic and vascular Patients and Settings Incidence of amputees. This finding was confirmed in a study finding Pain (%) no difference between amputees whose amputations were of Trauma-related amputees civilian or military origin.44 Cancer patients 12 48 CONCOMITANT TREATMENTS Chemotherapy before or at the time 74 of amputation The data on the influence of other treatments is contradictory. 44 Some studies have shown that radiotherapy and chemother- Chemotherapy after amputation 12 apy do not influence the incidence of chronic pain.9 However, No chemotherapy other studies have shown a higher incidence of chronic pain in patients who received chemotherapy and/or radiotherapy.8,27 Modified from Smith J, Thompson JM: Phantom limb pain and Smith et al28 point out that it is difficult to unravel the rela- chemotherapy in pediatric amputees. Mayo Clin Proc 1995;70:357–364. tionship between the different treatments and pain because of confounding factors such as age. In a study from the Mayo Clinic of children having limb amputations for either trauma or cancer, Smith and

262 SECTION IV • Postoperative Pain Management in Specific Clinical Settings of remembering. Several studies comparing pain reports by Bach et al,55 patients who were to undergo lower limb recorded in the perioperative period with reports of patients’ amputation were given analgesia by epidural local anesthetic memories of their pain several months later show poor cor- and opioid for 72 hours preoperatively. This study reported relation. It is therefore important that studies be prospective that the procedure reduced the incidence of phantom pain and that valid pain assessments be made in the perioperative at 1 year, but there were methodological problems. Nikolajsen period. Unfortunately, few studies fulfill these criteria, but et al56 subsequently conducted a randomized, double-blind, when they have been met, the incidence of chronic postsur- controlled trial to investigate the matter further. They showed gical pain does correlate with postoperative pain intensity.47 no benefit in reduction of phantom pain and no change in hyperalgesia, allodynia, or wind-up–like pain.57 Subsequent Adequate treatment of pain around the time of the oper- studies have also failed to show any convincing evidence that ation is correlated with a lower incidence of chronic pain treating pain prior to amputation or other forms of surgery after surgery. Whether there is a causal relationship is not yet prevents long-term pain. clear. It is reasonable, however, to assume with our current level of knowledge that we should take all possible steps Many studies have shown that pain before amputation is to minimize perioperative pain to try to prevent long-term a risk factor for chronic phantom pain. We must not aban- problems. don this important line of research, because phantom pain is usually resistant to treatment, so prevention is vital. The Choice of Anesthesia and Analgesia in Reducing fact that no clinical effect for preemptive analgesia has been Chronic Pain demonstrated should not blind us, however, to the possibility that it might be possible to reduce long-term problems by Many studies have looked at the influence of anesthetic tech- treating pain adequately perioperatively. It may be that the nique on short-term postoperative pain. Two studies have methods used in previous studies were inadequate to reduce examined pain for 10 days after surgery for which patients afferent input sufficiently. Perhaps using combinations of drugs were randomly allocated to receive either local anesthesia or may make it possible to reduce chronic pain after surgery. general anesthesia. In a study on patients undergoing hernia repair, Tverskoy et al48 showed that patients who received Several studies have investigated giving drugs preopera- either local anesthetic block and general anesthesia or spinal tively with the aim of reducing pain in the postoperative anesthesia had significantly less pain at 2 days than those period, including gabapentin,58–61 NSAIDs,62 fentanyl and who received only general anesthesia. At 10 days after ketamine,63 local anesthetic blocks,64–66 and anesthetic blocks operation, the group that had general anesthesia with local in combination with NSAIDs,67 and clonidine and ketamine.68 anesthetic still had significantly less pain than the general The results are contradictory, and there is a need for large anesthesia alone group. randomized controlled trials, although the methodological problems should not be underestimated. In an elegant study of pain after tonsillectomy and ade- noidectomy in children, Jebeles et al49 showed not only a Pain after injury is mainly a hyperalgesic phenomenon. decrease in pain scores but functional improvement in swal- There is evidence that lidocaine infusion reduces secondary lowing up to 10 days postoperatively in the children who but not primary hyperalgesia caused by thermal injury, received a preoperative local anesthetic infiltration. It is rea- presumably through a spinal effect.69 There is also evidence sonable to assume that the local anesthetic given at the time that ketamine given perioperatively reduces postoperative of surgery protected the nervous system from the afferent hyperalgesia.68 These are both promising lines for further nociceptive barrage during and immediately after the opera- research. tion. This protection may prevent the sensitization that leads to chronic pain. Not all studies comparing regional anesthe- PREOPERATIVE SCREENING sia with general anesthesia show such benefit, however.50 OF HIGH-RISK PATIENTS In a study of chronic pain after cesarean section, patients The presence of genetic risk factors opens up the possibility who had chronic pain were more likely to have had general of screening. Patients who are deemed to be at particular anesthesia rather than epidural anesthesia and had a higher risk could be prioritized to receive the best possible manage- recall of severe postoperative pain.51 ment to minimize that risk. There may be linked genetic factors, and many people working in this field believe that Chronic pain after vasectomy is common, but the results patients with other medical problems are more likely to of comparisons of local anesthesia with general anesthesia experience chronic pain after surgery. Kalkman et al,70 study- are contradictory.52,53 ing the factors predisposing to severe postoperative pain, showed that younger age, female sex, higher level of preop- Prevention in the Preoperative Period erative pain, larger incision size, and type of surgery (for example, abdominal or orthopedic) were independent pre- PREOPERATIVE ANALGESIA dictors. Another approach to preoperative screening might be to assess the response to heat stimulation.71 The finding that preoperative pain and perioperative pain are associated with a higher incidence of chronic postsurgical As mentioned earlier, patients’ beliefs about the cause pain led researchers to try delivering analgesia to patients and onset of their pain can influence the severity of pain and prior to surgery. Animal work suggesting that pretreating with its impact on their lives. Education therefore has an impor- analgesics reduced changes in the nervous system formed tant role to play in minimizing the problem of pain after a theoretical basis for this approach.54 In a much-quoted study surgery, especially because it seems increasingly obvious that the pain is not usually the surgeon’s fault.

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264 SECTION IV • Postoperative Pain Management in Specific Clinical Settings 49. Jebeles JA, Reilly JS, Gutierrez JF, et al: Tonsillectomy and adenoidec- 61. Dierking G, Duedahl TH, Rasmussen ML, et al: Effects of gabapentin tomy pain reduction by local bupivacaine infiltration in children. Int J on postoperative morphine consumption and pain after abdominal Pediatr Otorhinolaryngol 1993;25:149–154. hysterectomy: A randomised, double blind study. Acta Anaesthesiol Scand 2004;48:322–327. 50. McCartney CJL, Brull R, Chan VWS, et al: Early but not long-term benefit of regional compared with general anesthesia for ambulatory 62. Priya V, Divatia JV, Sareen R, Upadhye S: Efficacy of intravenous keto- hand surgery. Anesthesiology 2004;101:461–467. profen for pre-emptive analgesia. J Postgrad Med 2002;48:109–112. 51. Nikolajsen L, Sorensen HC, Jensen TS, Kehlet H: Chronic pain after 63. Katz J, Scmid R, Snijdelaar DG, Coderre TJ, et al: Pre-emptive analgesia Caesarean section. Acta Anaesthesiol Scand 2004;48:111–116. using intravenous fentanyl plus low-dose ketamine for radical prosta- tectomy under general anesthesia does not produce short-term or long- 52. McMahon AJ, Buckley J, Taylor A, et al: Chronic testicular pain follow- term reductions in pain or analgesic use. Pain 2004;110:707–718. ing vasectomy. Brit J Urol 1992;69:188–191. 64. Katz J, Clairoux M, Kavanagh BP, et al: Pre-emptive lumbar epidural 53. Paxton LD, Huss BK, Loughlin V, Mirakhur RK: Intra-vas deferens anaesthesia reduces postoperative pain and patient-controlled morphine bupivacaine for prevention of acute pain and chronic discomfort after consumption after lower abdominal surgery. Pain 1994;59:395–403. vasectomy. Brit J Anaesth 1995;74:612–613. 65. Aguilar JL, Rincon R, Domingo V, et al: Absence of an early pre- 54. Woolf CJ, Chong M: Preemptive analgesia—treating postoperative pain emptive effect after thoracic extradural bupivacaine in thoracic surgery. by preventing the establishment of central sensitisation. Anesth Analg Br J Anaesth 1996;76:72–76. 1993;77:362–379. 66. Gill P, Kiani S, Victoria BA, Atcheson R: Pre-emptive analgesia with 55. Bach S, Noreng MF, Tjellden NU: Phantom limb pain in amputees local anaesthetic for herniorrhaphy. Anaesthesia 2001;56:414–417. during the first 12 months following limb amputation, after preoperative lumbar epidural blockade. Pain 1988;33:297–301. 67. Espinet A, Henderson DJ, Faccenda KA, Morrison LMM: Does pre- incisional thoracic extradural block combined with diclofenac reduce 56. Nikolajsen L, Ilkjaer S, Christensen JH, et al: Randomised trial of epidural postoperative pain after abdominal hysterectomy? Br J Anaesth bupivacaine and morphine in prevention of stump and phantom pain 1996;76:209–213. in lower limb amputation. Lancet 1997;350:1353–1357. 68. De Kock M, Lavand’homme P, Waterloos H: Balanced analgesia in the 57. Nikolajsen L, Ilkjaer S, Jensen TS: Effect of preoperative extradural bupi- perioperative period: Is there a place for ketamine? Pain 2001;92: vacaine and morphine on stump sensation in lower limb amputees. Brit 373–380. J Anaesth 1998;81:348–354. 69. Holthusen H, Irsfeld S, Lipfert P: Effect of pre- or post-traumatically 58. Fassoulaki A, Patris K, Sarantopoulos C, Hogan Q: The analgesic effect applied lidocaine on primary and secondary hyperalgesia after experi- of gabapentin and mexiletine after breast surgery for cancer. Anesth mental heat trauma in humans. Pain 2000;88:295–302. Analg 2002;95:985–991. 70. Kalkman CJ, Visser K, Moen J, et al: Preoperative prediction of severe 59. Dirks J, Fredensborg BB, Christensen D, et al: A randomised study of postoperative pain. Pain 2003;105:415–423. the effects of single-dose gabapentin versus placebo on postoperative pain and morphine consumption after mastectomy. Anesthesiology 71. Werner MU, Duun P, Kehlet H: Prediction of postoperative pain by 2002;97:560–564. preoperative nociceptive responses to heat stimulation. Anesthesiology 2004;100:115–119. 60. Rorarius MGF, Mennader S, Suominen P, et al: Gabapentin for the prevention of postoperative pain after vaginal hysterectomy. Pain 2004; 72. Reuben S: Preventing the development of complex regional pain 110:175–181. syndrome after surgery. Anesthesiology 2004;101:1215–1224.

INDEX Note: Page numbers followed by f, t, and b indicate figures, tables, and boxes, respectively. A Adrenal hormones, in stress response, 29-30, 29t Analgesia, different types of, patient outcome α2-Adrenergic agonists. See also Clonidine. and, 74-79 Abdominal outpatient surgery, pain management for, 253-254 as adjuncts in peripheral nerve blockade, epidural, after cesarean section, 225-228, 155-156, 156t 225b, 226f, 226t, 227f, 228t Abstinence syndrome, in drug-dependent patients, 239, 240 for pain relief, 201-202 “catheter-incision congruent,” 79 β-Adrenergic drugs, for alcohol withdrawal, 241 for prevention of complex regional pain Acamprosate, in alcohol withdrawal, 243 Adrenocorticotropic hormone (ACTH), in stress Accufuser, for delivery of analgesia, 250, 252f, 254 syndrome, 53 Acetaminophen, for cesarean section response, 29, 29t, 30 in children, 213-214 Adrenomedullary sympathetic system, in stress perioperative, for stump and phantom analgesia, 235 for children, 212 response, 27, 29f pain, 51 for pain in outpatient surgery, 250, 252, 252t Adverse drug reactions, 64, 64f. See also Drug postoperative pulmonary complications patient outcome and, 74-75 plus codeine, 141t interactions. and, 159 plus dextropropoxyphene, 141t Advisories, definitions of, 12, 13b with opioids. See Opioids, epidural. Acid-sensing ion channels, 38 Afferent nerve impulses, in general anesthesia, multimodal, 96, 97, 182-192 ACTH, in stress response, 29, 29t, 30 advantages of, 182, 184b, 184f Acupuncture, for pain relief, 197-198, 199f 27, 110 agents commonly used for, 184b, Acute pain services, 80-81, 96, 97f in inflammatory response, 30 as resource for education and training, 123-124 to dorsal horn, 34, 35f 188-189, 189t audits of, 123 Age, chronic pain and, 260 antihyperalgesia with, 186, 186f, 186t cost-effectiveness of, 120 opioid pharmacokinetics and, 130 complementary and alternative medicine for children, 216 Air embolism, in location of epidural space, 214 future trends in, 123-124 Alcohol, dependence on, pharmacological modalities in, 190 implementation of, 120-122, 121t cost-effectiveness of, 191 nurses’ role in, 122-123 considerations with, 241-242 cox-2 dilemma in, 190 organization of, 121-122 treatment of, 243 current opinions and dilemmas in, patient outcome and, 119-120 with aspirin and NSAID use, 174 patient-controlled analgesia used in, 148 Alcohol withdrawal, in alcohol-dependent 188-189 prevalence of, 118, 119t patients, 241 disadvantages of, 182-184 problems with, 122 Aldosterone, in stress response, 30 drug combinations used in, 191-192, 191f quality improvement in, 123 Alerts, definitions of, 12, 13b requirements of, 119 Alfentanil, in ambulatory surgery patients, 139 regulation of, 185 structure of, 118-119 pharmacokinetics of, 129t selection of, 189, 190b surgeons’ role in, 123 in patient-controlled analgesia, 149t drug-sparing and, 182 Acute renal failure, postoperative, nonsteroidal Alleles, 63 evidence-based principles and, 182 Allodynia, in central sensitization, 36, 37, 47, 259 fixed-dose vs. flexible-dose combinations anti-inflammatory drug use and, 170 Alternative medicine, for pain relief, 190 Addiction, definition of, 240-241, 240f nonpharmacological techniques of, 197-200 in, 184-185, 184t, 185f pharmacological agents used in, 198t, for cesarean section pain, 187, 235 opioid, 242, 243-244 future directions in, 191-192, 191f opioid tolerance and, 241, 244, 245, 246. 200-205, 201t in outpatient surgery, 249-250 See also Tolerance, opioid-induced. Alvimopan, for opioid-induced delayed gastric patient outcomes with, 79-80, 187-188 opioid-induced hyperalgesia in, 85, 88f preemptive, 188 perioperative treatment plan for, 244-247 emptying, 133 rationale for, 182, 183f, 183t, 184b postoperative pain treatment for, 247 Amantadine, for neuropathic pain, 47 safety of, 183 Ambulatory surgery, parenteral opioids in, side effects of, 191 postoperative pain management in, 247 vs. monotherapy, 186, 187f postoperative treatment of, 243-244 138-139 nonconventional, nonpharmacological rekindling of in postoperative period, 243, 247 postoperative pain management in, in specific Adenomatous Polyp Prevention Trial on Vioxx techniques of, 197-200, 198t procedures, 253-256 pharmacological agents used in, 198t, (APPROVe), 172 principles of, 249-253 Adenomatous Prevention with Celecoxib (APC) American Society of Anesthesiologists, 200-205, 201t definitions of, 12 number-needed-to-treat values of, Study, 172 practice guidelines of, 22 Adenosine, for pain relief, 200-201, 201t Amiodarone, CYP2D6 inhibition by, 67 191, 191f Adenosine triphosphatase, in peripheral Amitriptyline, for neuropathic pain, 56t preemptive, 72, 72f, 73f, 74, 96 AMPA (alpha-amino-3-hydroxy-5-methyl- sensitization, 42 isoxazole-4-propionic acid) receptors, controversy in, 110-113, 111f-113f Adhesion molecule expression, in inflammatory 34, 36, 37f, 72 definition of, 110-111 Amphetamines, dependence on, 242 history of, 110 response, 31 Amputation, phantom pain and stump pain in outpatient surgery, 250 with, 51, 51t, 260, 261 multimodal, 188 timing of, evidence-based reviews of, 113-115, 114t studies of, 111-112, 111f, 112f 265

266 Index Analgesia (Continued) Antiepileptic drugs, for neuropathic pain, Blinding, in randomized controlled trials, 7 preventive, evidence-based reviews of, 54t-55t, 58 Body mass index, 130 113-115, 114t Bolam doctrine, 15 studies of, 112-113, 113f, 114f Antihistamines, for pain relief, 201t, 205 Bone growth, inhibition of, nonsteroidal protocol-based, in outpatient surgery, Antihyperalgesic drugs, multimodal analgesia 250, 251f anti-inflammatory drug use and, 175, 175b regional and peripheral, opioids for, 144, and, 186, 186f Bowel function, with patient-controlled 144t, 145b opioids with, fixed-dose and flexible-dose patient outcome and, 75-79 analgesia, 151 vs. other analgesic methods, 79 combinations of, 186, 186t Brachial plexus block, adenosine with, 200 systemic, patient outcome and, 74-75 Anxiety, pain and, 102 timing of, in preemptive method, 111-112, Appendectomy, outpatient, pain management clonidine and neostigmine as adjuncts with, 111f, 112f 156, 156t in preventive method, 112-113, for, 254 113f, 114f Arachidonic acid, 161 in children, 214 postoperative pain prevention and, Arm, outpatient surgery on, 254-255, 255f opioids as adjuncts with, 155 109-110 Arthroplasty, nonsteroidal anti-inflammatory Bradykinin, in peripheral sensitization, Analgesics, nonopioid, genetic influences on, 68 drug use with, 168-169, 169t 36, 44, 45f number-needed-to-treat values of, bleeding risk and, 174 nociceptive pain and, 37-38 191-192, 191f Arthroscopic procedures, nonsteroidal anti- Brain, neurobiologic changes in, after injury, inflammatory drug use with, 167-168, 168t Anesthesia, epidural, for prevention of complex outpatient, pain management for, 259-260 regional pain syndrome, 53 in opioid-addicted patients, 247 255-256, 256f Brain-derived neurotrophic factor, in peripheral in children, 213-214 rofecoxib in, 190 nerve injury, 44 continuous infusions of, 214 Aspirin, bleeding risk with, 173-174 Breast surgery, chronic pain and, 260, 261, 261t insertion sites for, 214 for postoperative pain, patient outcome and, Bretylium, in intravenous regional blockade, for prevention of complex regional pain general, afferent injury transmission and, 74-75 syndrome, 52 27, 110 gastrointestinal damage with, 171 Buccal-transmucosal administration, in outpatient surgery, 252-253, 252t of opioids, 131 in outpatient surgery, 250 plus codeine, perioperative use of, 141t Bupivacaine, in brachial plexus block in in studies of preemptive analgesia, prostaglandin synthesis and, 162 children, 214 Atropine, in intravenous regional blockade, for in preemptive analgesia, 112f 113, 113f with hydromorphone, in children, 214 vs. local anesthesia, chronic pain and, 262 prevention of complex regional pain Buprenorphine, addiction to, postoperative vs. regional anesthesia, complex regional syndrome, 52 recovery program for, 247 Augmented facilitation, in neuropathic pain, for neuropathic pain, 57t pain syndromes and, 52, 53 46f, 48 for opioid addiction, 243-244 vs. spinal anesthesia, 154-155 Australia, use of guidelines in, 14b for patient-controlled analgesia, 231, 232t in opioid-tolerant or opioid-dependent Australian National Health and Medical Research perineuronal administration of, 144 Council, practice guidelines of, 22 Butorphanol, addiction to, postoperative patients, 245 Autonomic nervous system, in stress response, recovery program for, 247 preemptive multimodal, 113, 113f 27, 29f epidural, in cesarean section Axillary brachial plexus block, adenosine complex regional pain syndromes and, 53 with, 200 analgesia, 227 regional, 154-159 clonidine and neostigmine with, 156, 156t in preemptive multimodal analgesic in children, 214 advantages and disadvantages of, 250, 251b opioids with, 155 therapy, 188 complex regional pain syndromes and, Axillary catheter technique, in outpatient surgery, 255 C 52-53 Axonotmesis, 50 for hip fracture, vs. general anesthesia, Caffeine, for pain relief, 201t, 204-205 B Calcitonin, for neuropathic pain, 53 154-155 Calcitonin gene-related peptide, in complex in children, 213-214 B1 receptor, in peripheral sensitization, 44 in elderly, 222-223, 223t nociceptive pain and, 37, 38 regional pain syndrome, 53 in outpatient surgery, 250 in nociception, 72 nonsteroidal anti-inflammatory drug use B2 receptor, in peripheral sensitization, 44 in pain transduction, 34 nociceptive pain induced by, 37-38 Calcium, as second messenger, 38f and, bleeding risk and, 174 in central sensitization, 36, 38f postoperative cognitive dysfunction and, Baclofen, for pain relief, 201t, 205 in peripheral sensitization, 44 Barbiturate dependence, pharmacological Calcium ion permeability, B2 receptor 156-157 postoperative pulmonary complications considerations with, 242 activation and, 38 Benzodiazepines, dependence on, Canada, acute pain services in, 118 and, 157-159, 158f vs. general anesthesia, 154-155, 250, 251b pharmacological considerations with, 242 use of guidelines in, 14b for alcohol withdrawal, 241 Canadian Task Force on Periodic Health complex regional pain syndromes and, in opioid-tolerant patients, 246 52, 53 postoperative cognitive dysfunction and, 157 Examination, study design withdrawal from, 242 classification by, 18t spinal, in elderly, 222-223, 223t Bias, in patient selection, in randomized Cannabinoids, for pain relief, 201t, 205 in preemptive analgesia, 113, 113f Cannabis, dependence on, 242-243 vs. general anesthesia, 154-155 controlled vs. observational studies, 2 Capsaicin, for pain relief, 201t, 205 in search for evidence, 1-2 Carbamazepine, for neuropathic pain, 54t Anesthesiologist, role of in acute pain service, outcomes research and, 2 Cardiff Palliator, 148 121-122, 121t publication, 2, 191 Cardiovascular effects, of nonsteroidal randomization and, 2 anti-inflammatory drugs, 171-173, 173b, Anesthetist, role of in treatment of neuropathic selection, 2 173t, 190 pain, 48-50, 49b, 49t Bieri Faces Pain Scale, in children, 212 of opioids, 134 Biliary tract pressure, opioid administration Case reports, as evidence, 6, 6f Angiotensin II, in stress response, 30 Catechol-O-methyltransferase (COMT), genetic Animal data, on opioid-induced hyperalgesia, and, 134 polymorphisms and, 68 Bladder function, opioid administration and, 134 Categorical pain scales, 103 85, 86f, 87f, 88f, 89-91, 89f, 90f Bleeding, nonsteroidal anti-inflammatory drug Antibody, in neuropathic pain, 47-48 Anticholinergic drugs, postoperative cognitive use and, 173-174, 174b dysfunction and, 157 Anticonvulsants, for pain relief, 201t, 204 Antidepressants, for neuropathic pain, 56t, 58 for pain relief, 201t, 204 Antidiuretic hormone, in stress response, 27, 29f, 29t, 30

Index 267 Catheter(s), axillary, 255 Chronic pain, 71-72, 73f, 74, 191. Corticotrophin-releasing hormone (CRH), Contiplex, 255, 256 See also Neuropathic pain. in stress response, 27, 29f, 29t infraclavicular, 254-255, 255f stimulating, 255, 256 causes of, 259 Cortisol, in stress response, 29, 29t central sensitization and, 84 Cost-effectiveness, of acute pain services, 120 Caudal epidural block, in children, 213 hyperalgesia and, 84 Causalgia. See Complex regional pain management of, integration of acute pain of multimodal analgesic therapy, 191 Cross-addiction, 241, 243 syndrome. services with, 124 Cuthbertson, phases of in response CB-1 receptor, in addiction, 244 mechanisms of, 259-260 Celecoxib, cardiovascular toxicity and, poorly controlled postoperative pain and, to surgery, 27 Cyclic guanosine monophosphate, B2 receptor 171b, 172 71-72, 261-262 CYP2D6 inhibition by, 67 preoperative pain and, 52 activation and, 38 for outpatient surgical pain, 253, 253t Cyclooxygenase inhibitors, in elderly, 222 for postlaparoscopic gynecological surgical prediction of postoperative pain and, 104, 107, 110 NSAIDs as, 161, 162, 173-174, 174b pain, 165 antihypertensive drugs and, 172-173 genetic influences on, 68 prevention of, 262-263 bone repair and, 175, 175b Celecoxib Long-term Arthritis Safety Study risk factors for, 260-262 cardiovascular toxicity and, 171-172, undertreatment of pain and, 191 171b, 173t (CLASS), 171, 172 Circumcision, outpatient, 254 gastrointestinal toxicity and, 171, 171b Central nervous system function, in elderly, Cirrhosis, nonsteroidal anti-inflammatory in multimodal analgesic therapy, 187, 189t, 190 219, 220t drug-associated renal toxicity and, 170 in outpatient surgery, 253, 253t Central pain, ascending pathways of, 34-35, 36f Clinical trials, of pharmaceutical companies, renal effects of, 170 descending inhibitory pathways of, 36-37, reporting of, 191 Cyclooxygenase-1 (Cox-1), 161, 162 36f-38f Clonidine, for alcohol withdrawal, 241 Cyclooxygenase-2 (Cox-2), 161, 162 Central sensitization, 36-37, 37f, 38f for cesarean section analgesia, 227, 229 bone repair and, 175, 175b acute and late phases of, 46f for pain relief, 201-202, 201t in central sensitization, 46f, 47 chronicity of pain and, 84 in intravenous regional blockade, for in inflammatory response, 31, 31t forms of, 47 in peripheral sensitization, 44, 45f hyperalgesia and, 84 prevention of complex regional pain in post-thoracotomy pain, 164 in deafferentation pain, 51 syndrome, 52 in preemptive analgesia, 115 in neuropathic pain, 42f, 46f, 47-48, 259 in peripheral nerve blockade, 155-156, 156t inhibitors of, concerns about safety of, 96 in thermal injury, 259 intrathecal, 229 mechanisms of, 47 with levobupivacaine or ropivacaine, in in multimodal analgesic therapy, 187, postoperative pain and, 72f brachial plexus block in children, 214 189t, 190 prevention of, 109 with patient-controlled epidural analgesia, by preemptive analgesia, 72, 72f, 73f, for cesarean section pain, 227 in outpatient surgical pain, 253, 253t 74, 110 Coagulation response, to surgery, 32 Cyclooxygenase-3 (Cox-3), 161 systemic opioid blockade and, 110 Cocaine, dependence on, pharmacological Cytochrome P450, CYP2C9 isoenzyme of, considerations with, 242 Cerebrospinal fluid, opioid administration Cochrane Collaboration, 2, 9 drugs metabolized by, 65, 65t into, 132 Cochrane Collaborative Review Groups, 191 in efficacy of nonsteroidal anti- Cochrane Library, 185, 191 Cesarean section, epidural analgesia after, Cochrane protocol, 124 inflammatory drugs, 68 225-228, 225b, 226f, 226t, 227f, 228t Codeine, effectiveness of, 65-66 CYP2C19 isoenzyme of, drugs metabolized in outpatient surgery, 253, 253t intrathecal analgesia after, 228-231, 228t, metabolism of, 130 by, 65, 65t 229f, 230f oral, 139, 140t, 141t CYP2D6 isoenzyme of, drugs metabolized pharmacokinetics of, 129t intravenous patient-controlled analgesia Cognitive impairment, in elderly, 220 by, 65, 65t after, 231-233, 232t, 233f postoperative, regional anesthesia and, in efficacy of nonsteroidal anti- 156-157 multimodal analgesic therapy after, 187, 235 risk factors for, 157 inflammatory drugs, 68 nonsteroidal anti-inflammatory drugs after, Cognitive-behavior therapies, for addictions, 244 individual variations in gene for, 65, 66t Cold therapy, for pain relief, 200 metabolism of codeine and, 130 166, 167t, 231-233, 232t, 233-235, Color Analogue Scale, in children, 212 pharmacological inhibitors of, 67, 67b 233f, 234f Complement cascade, in neuropathic pain, 48 CYP2D9 isoenzyme of, in efficacy of other oral adjunctive drugs after, 235 Complementary medicine, in pain c-fos, in central sensitization, 37, 37f management, 190. See also Analgesia, nonsteroidal anti-inflammatory Chemokines, in inflammatory response, 31t nonconventional. drugs, 68 Children, development of pain processing in, Complex regional pain syndrome, neuropathic individual drug-metabolizing variations in, 211-212 pain in, 52-53 65-66, 65t, 66t neostigmine as local anesthetic-sparing orthopedic surgery procedures and, 52b, 263 metabolism of codeine and, 130 agent in, 202 types of, 52b Cytokines, in inflammatory response, 30 nonsteroidal anti-inflammatory drug Compression nerve injury, 49-50 use in, 174 Confounding, bias and, 2 D other pain therapies in, 216 Congestive heart failure, nonsteroidal anti- pain assessment and measurement in, 212 inflammatory drug use and, 170, 173, 173b Dantrolene, for pain relief, 201t, 204 pain side effects in, treatment of, 216 Consensus, in assessment of evidence, 3 Database, in search for evidence, 2 pain therapy in, 212-216 Consolidated Standard of Reporting Trials Deafferentation pain, 51, 259 phantom pain in, 261t (CONSORT) Statement, 185, 191 Death, patient-controlled analgesia and, 152 postoperative monitoring in, 216 Contiplex catheter, in outpatient surgery, Deep venous thrombosis, in regional vs. regional anesthesia in, 213-214 255, 256 Cholecystectomy, chronic pain following, Control groups, in hierarchy of evidence, 6, 6f general anesthesia, 154, 155 causes and risk factors for, 51-52, 261 in randomized controlled trials, 7 local anesthetic–based analgesia and, 78, 78f laparoscopic, chronic pain with, 261 in studies of preemptive analgesia, 111-112 Delirium, in elderly, 220 multimodal analgesic therapy for, 187 Coronary bypass, coxib administration and, postoperative, regional anesthesia and, 157 nonsteroidal anti-inflammatory drug use 172, 173t Delirium tremens, 241 Delivery, cesarean, epidural opioids for, 226t with, 165, 165b, 166t nonsteroidal anti-inflammatory drug use outpatient, 254 port site pain with, 51 with, 167 Chronic conditions, in elderly, pain assessment Dementia, pain assessment and, 221 and, 220 Dental pain, acupuncture for, 198 Despiramine, for neuropathic pain, 56t Developmental pain, 211-212

268 Index Dextroamphetamine, for pain relief, 201t, 205 E F Dextromethorphan, genetic influences on, 68 Ear, nose, and throat procedures, outpatient, Face, Legs, Activity, Cry, Consolability (FLACC) in preemptive analgesia, 115 pain management for, 254 pain assessment tool, 212 Dextropropoxyphene, in multimodal analgesic Ecstasy (MDMA), 242 Facilitation, augmented, in neuropathic pain, therapy, 187-188 Ectopic excitability, of neurons, pain and, 46f, 48 oral, 139, 141t Diacetylmorphine, oral, 139, 140t 44, 47 Fascia iliaca compartment block, Diamorphine, epidural, in cesarean section Efferent stimuli, in stress response, 27, 29f in children, 215 Elderly, analgesic drugs used in, 221-223 analgesia, 227 FDA (Food and Drug Administration), regulation intrathecal, 142 assessment of pain in, 220-221, 220b of combination therapies by, 185 multimodal analgesia in, 183-184 in cesarean section analgesia, 228 nonpharmacologic techniques in, 223 Femoral nerve block, in children, 214-215 Diclofenac, for arthroscopic procedures, 167 opioid pharmacokinetics in, 130 Fenoprofen, half-life and plasma concentration pain management in, 219-223 for cesarean section analgesia, 233-234 patient education in, 221 of, 162t for pain relief in thoracotomy, 163 patient-controlled analgesia in, Fentanyl, epidural, dose of, 142t, 149t for postlaparoscopic gynecological surgical 222, 222t for cesarean delivery, 226t pain, 164 physiologic changes affecting drug handling for cesarean section analgesia, for preemptive multimodal analgesia, 188 half-life and plasma concentration of, 162t in, 219-220, 220t 226-227, 227f postoperative hemostasis and, 174 Electrodiagnostic studies, for neuropathic in preemptive analgesia, 111f, 112f prostaglandin synthesis and, 162 plus bupivacaine, 142t Dihydrocodeine, oral, 139, 141t pain, 49 for neuropathic pain, 57t Disability, chronic pain and, 260 EMBASE, 2 hyperalgesia induced by, in animal studies, Disinhibition, of pain, 46f, 48, 128 Emotional factors, immune response and, in Disulfiram, for alcohol abuse, 243 85, 86f, 87f, 90, 90f Dopamine, in drug addiction, 240-241 stress response, 30 in patient-controlled analgesia, 231 Dorsal horn, afferent input to, 34, 35f Endomorphins, 127 in central sensitization, 36-37, 37f, 38f, 47 β Endorphins, in stress response, 27, 29t dosing guidelines for, 149t in neuropathic pain, 46f, 47-48 Endothelial permeability, in inflammatory in children, 213, 213t in nociception, 72 intrathecal, for cesarean section analgesia, in sensory nerve impulse transmission, 34 response, 30, 31, 31f Dorsal root ganglion, axonal injury in, sodium Epidural analgesia. See Analgesia, epidural; 228-229, 228t, 229f intravenous, 138, 138b, 140t channel expression and, 38, 47 Opioids, epidural. metabolites of, 130 immune cells in, in neuropathic pain, 48 Epidural anesthesia, for prevention of complex oral, 139, 140t Dorsolateral funiculus, in modulation pharmacokinetics of, 129t regional pain syndrome, 53 of pain, 36 in children, 213-214 in patient-controlled analgesia, 149t Droperidol, in intravenous regional blockade, transdermal, 74 continuous infusions in, 214 Flurbiprofen, bone healing and, 175 for prevention of complex regional pain insertion sites for, 214 Food and Drug Administration (FDA), syndrome, 52 Epidural block, in children, 213, 214 Drug(s), adjunctive, in multimodal analgesic Epidural space, in elderly, 222 regulation of combination therapies by, Epinephrine, for cesarean section analgesia, 185 therapy, 189t epidural opioids with, 227 Foot and ankle, outpatient surgery on, in opioid-tolerant patients, 246 intrathecal, 229 256, 256f, 257f with peripheral nerve blockade, 155-156, in stress response, 27, 29t Frontal cortex, 35 Ethnic groups, drug-metabolizing capacity in, Functional pain, 41f, 46t 156t, 157t 65, 66t Funiculus, dorsolateral, in modulation adverse reactions to, genetic variables and, Etodolac, prostaglandin synthesis and, 162 of pain, 36 Etoricoxib, in outpatient surgery, 64, 64f 253, 253t G risk factors for, 64 Europe, use of guidelines in, 14b metabolism of, cytochrome P450 isoforms European Medicines Evaluation Agency G protein-coupled systems, in nociceptive (EMEA), regulation of combination pain, 38 and, 65-66, 65t, 66t therapies by, 185 genetics of, 64-66 Evidence, access to, 9-10 inwardly rectifying potassium channels in, 38 topical, for neuropathic pain, 58, 58t assessment of, 2-3, 6-9 opioid receptors as, 128 withdrawal of, 240 classification of, 19t Gabapentin, antihyperalgesic properties of, alcohol withdrawal and, 241-242 hierarchy of, 6, 6f, 18b in drug-dependent patients, 239-240, poor quality of, 5 186, 186f search for, 1-2 for neuropathic pain, 54t 241, 243 strength of, grading of, 3, 3t, 19t preoperative, for prevention of postoperative Drug dependence, 239-247 Evidence-based medicine, components of, 1 data resources for, 20t, 21t pain, 262 definitions of, 239-241 definition of, 1 Galanin, in nociception, 72 drug abstinence programs and, 243 general-purpose sources for, 9t Gamma-aminobutyric acid (GABA), drug withdrawal in, 239-240, 241, 243 guideline development and use in, 15, 16b, pain management in, perioperative plan for, benzodiazepines and, 241, 242 17, 17b, 18, 18b, 18t, 19t disinhibitory action of opioids on, 128 244-247 practice of, 4 in modulation of pain, 36 risks of mismanagement in, 239 principles of, 1-4 in neuropathic pain, 48 pharmacological considerations with, 241- search for evidence in, 1-2 Gastric emptying, delayed, opioid-induced, 133 Excitability, ectopic, pain and, 44, 47 Gastritis, in elderly, from nonsteroidal 243. See also Tolerance, opioid-induced. increased, in central sensitization, 47, 259 physical, 239-240 anti-inflammatory drug use, 221 treatment for, 243-244 with opioids, 84 Gastrointestinal effects, of nonsteroidal Drug interactions, genetic polymorphisms and, Expert opinion, as evidence, 6, 6f Extensive metabolizers, 65, 66 anti-inflammatory drugs, 66-67 External validity, of randomized controlled 170-171, 171b in elderly, from nonsteroidal anti- in elderly, 221 trials, 8 opioid-induced, 133-134 inflammatory drug use, 221 Extracellular signal-related kinase, 32 Gastrointestinal motility, postoperative, in multimodal analgesia, 184 Extracellular volume, in stress response, 30 neuraxial blockade and, 77, 78f Dynorphin, in central sensitization, 46f, 47 opioid-induced, 133 spinal, in μ-opioid receptor binding, 85 Gemstar Yellow programmable infusion Dysrhythmia, postoperative, local pump, for delivery of analgesia, 250, 252f, 254 anesthetic–based analgesia and, 77-78, 79f

Index 269 Gender, opioid pharmacokinetics and, 130 Hemodynamic depression, with patient- Immunoglobulin G, in neuropathic pain, 47-48 pain prevalence and, genetic influences on, 68 controlled analgesia, 151 Immunoglobulin M, in neuropathic pain, 47 Indomethacin, for cesarean section analgesia, 235 Gene(s), candidate, in pain perception and Hernia, inguinal, repair of, neuropathic pain modulation, 68 with, 50-51, 261 for pain relief in thoracotomy, 163 outpatient, 253-254 half-life and plasma concentration of, 162t CYP2C9, 65, 65t, 68 Indoprofen, for obstetrical pain, 166 CYP2C19, 65, 65t Heroin, hyperalgesia induced by, in animal Infants, epidural analgesia in, 214 CYP2D6, 65, 66t, 67, 67b, 68, 130 studies, 85, 87f, 88f, 90, 90f opioid pharmacokinetics in, 130 CYP2D9, 68 Infection, epidural, in children, 216 expression of, in central sensitization, 46f, 47 withdrawal from, 242 Inflammation, peripheral sensitization and, Heterotopic ossification, nonsteroidal pain and, 44, 45f 42, 45f influencing neuropathic pain, 63 anti-inflammatory drug use and, 175 Inflammatory pain, 41f General anesthesia, afferent injury transmission High-motility group box protein 1, in ion channel activation in, 38 and, 27, 110 inflammatory response, 30 mediators of, in nociception, 72 in outpatient surgery, 250 Hip arthroplasty, nonsteroidal anti-inflammatory in studies of preemptive analgesia, 113, 113f in pain transduction, 45f vs. regional anesthesia, 250, 251b drug use and, bleeding risk and, 174 processing of, 183t Hip fracture, anesthesia for, regional vs. general Inflammatory response, nociceptor sensitivity complex regional pain syndrome and, 52, 53 techniques for, 154-155 and, 34, 35f Histamine, in inflammatory response, 31t to surgery, 30-32 vs. spinal anesthesia, for hip fracture, 154-155 Homeostasis, changes in after surgery, 27 Infraclavicular catheter techniques, in Genetics, basic principles of, 63, 64f Hormones, in stress response, 29-30, 29t Hydrocele, outpatient repair of, 254 outpatient surgery, 254-255, 255f chronic pain and, 261 Hydromorphone, epidural, dose of, 142t Inguinal hernia, repair of, neuropathic pain genomics and, 63-64 of drug metabolism, 64-66 in cesarean section analgesia, 227 with, 50-51, 261 Genomic variations, 63, 64f plus bupivacaine, 142t outpatient, 253-254 Geographic bias, in search for evidence, 2 in opioid-tolerant patients, 246 Inguinal paravascular technique, for nerve Glomerular filtration rate, nonsteroidal anti- in outpatient surgery, 253, 253t block in children, 214-215 in patient-controlled analgesia, dose of, 149t Inhibition, decreased, in neuropathic pain, inflammatory drug use and, 170 in children, 213, 213t 46f, 48, 128 Glucocorticoids, in stress response, 29-30, 29t pharmacokinetics of, 149t Injury, physiological response to, 27, 28f Glucose tolerance, in stress response, 29, 29t intrathecal, 142-143 Institute of Medicine, definitions of, 12 Glutamate, in central sensitization, 36, 37f, 38f intravenous, 138, 138b, 140t Insulin, in stress response, 29t, 30 oral, 139, 140t β2 Integrin, in inflammatory response, 31 in nociceptive pain transmission, 34 spinal, 141-142, 142t Intention-to-treat analysis, in randomized Glycine, in neuropathic pain, 48 Hyperalgesia, in central sensitization, 36, 37, controlled trials, 8 Glypican-1, in neuropathic pain, 48 47, 259 Intercellular adhesion molecule-1 (ICAM-1), in Google Scholar Search, 10 nonsteroidal anti-inflammatory drug action inflammatory response, 31 Government organizations, guideline Interleukin-1, in stress response, 27 and, 161, 162 Interleukin-1β, in central sensitization, 47 development by, 12 opioid-induced, 84-92 in inflammatory response, 31t Growth hormone, in stress response, 29, 29t in nociceptive pain, 38 Guanethidine, in intravenous regional definition of, 84 in peripheral sensitization, 44 evidence of, 85, 86f-89f, 89 Interleukin-6, in inflammatory response, 31t blockade, for prevention of complex in opioid addicts, 85, 88f in stress response, 27 regional pain syndrome, 52 mechanisms of, 84-85, 85b Interleukin-8, in inflammatory response, 31t Guidelines, benefits of, 13-14, 22t modulation of, 89-92, 89f-92f Interleukin-10, in inflammatory response, 31t components of, 16b postoperative, harmful effects of, 84 Interleukin-12, in inflammatory response, 31t definitions of, 12, 12b, 13b primary, 34 International Association for the Study development of, 12 secondary, 34, 47 of Pain, 137 in evidence-based medicine, 15, 16b, 17, treatment of, multimodal analgesia for, 186, Internet, access to evidence-based research and, 10 17b, 18, 18b, 18t, 19t 186f, 186t practice of evidence-based medicine and, 1, 4 policy statement of, 17b Hypertension, nonsteroidal anti-inflammatory sources of evidence and evidence-based effectiveness of, 21-22 implementation and enforcement of, 18, 20 drug use and, 172-173, 173b guidelines on, 18, 20t, 21t, 124 international, 13, 14b Hypnosis, for pain relief, 198-199 Interscalene block, in children, 214 legal considerations with, 15, 15b Hypothalamic-pituitary-adrenal axis, of stress maintenance and updating of, 20-21, 22b in outpatient surgery, 254 of U. S. Agency for Healthcare Quality and response, 27, 29f Intraoperative regional blockade, in children, 216 Hypothalamus, in central pain ascending Intraoperative suggestions, for pain relief, 200 Research, 71 Ion channel(s), in inflammatory pain, 38 on acute pain, 21-22, 124 pathway, 35, 36f on postoperative pain management, 124 in pain modulation, 36 in peripheral sensitization, 36 problems with, 14-15 in stress response, 27, 29-30, 29t of nociceptor peripheral terminal, 45f tasks of and approaches to, 16b Hypoxia, respiratory response to, opioid Iontophoresis. See also Transdermal Gynecological surgery, neostigmine in, 202 NSAID use in, in laparoscopic procedures, administration and, 133 administration. Hysterectomy, nonsteroidal anti-inflammatory for delivery of opioids, 131, 199-200 164-165, 165t for pain relief, 199-200 in nonlaparoscopic procedures, drug use with, 165-166, 166b Isobologram, in multimodal analgesia, 165-166, 166b I 184-185, 185f outpatient, 254 Ibuprofen, efficacy of, genetic influences on, 68 J H for obstetrical pain, 166 half-life and plasma concentration of, 162t Joint Commission on Accreditation of Healthcare providers, guidelines for, benefits in children, 212 Healthcare Organizations (JCAHO), acute of, 13-14 in outpatient surgery, 252t pain services and, 122 harm from, 14-15 Iliohypogastric nerve block, in children, 216 standards of, 71, 95t, 97 Health-technology assessment, 3 Ilioinguinal nerve block, in children, 216 Jun N-terminal kinase, 32 Heat sensitivity, in peripheral nerve injury, 44, Imipramine, for neuropathic pain, 56t Immune response, emotional factors and, in 45f, 47 Heat therapy, for pain relief, 200 stress response, 30 modulation of, in neuropathic pain, 47-48

270 Index K Local anesthetics, epidural, for postoperative Meperidine (pethidine) (Continued) pain, 76-79, 77f, 78f pharmacokinetics of, 129t, 149t Kallidin, nociceptive pain and, 37-38 postoperative cognitive dysfunction and, 157 Ketamine, for antihyperalgesic effect, 47, 186 in elderly, 222-223, 223t patient outcomes with, 77-79, 77f, 78f Mepivacaine, in brachial plexus block in for multimodal analgesia, 187, 188 postoperative mortality and complications children, 214 for pain relief, 201t, 202-203 for preemptive analgesia, 115 and, 77, 77f, 78f Meta-analysis, in assessment of evidence, 3 in elderly, 222 vs. systemic opioids, 76, 77, 77f of randomized controlled trials, 6, 6f in opioid tolerance, animal studies of, 89-91, with spinal opioids, 142, 142t vs. systematic review, 18 for cesarean delivery, postoperative epidural 89f, 90f Metabolic response, to surgery, 28f human studies of, 91-92, 91f morphine and, 226 Metabolites, of opioids, 129t in opioid-tolerance, 246 in children, in brachial plexus block, 214 Ketanserin, for neuropathic pain, 53 analgesic efficacy of, 129-130 for prevention of complex regional pain in fascia iliaca compartment block, 215 Methadone, for neuropathic pain, 57t in femoral nerve block, 215 syndrome, 52 in interscalene block, 214 for opioid addiction, 243-244 Ketoprofen, for obstetrical pain, 166, 235 in elderly, 221, 222-223, 223t opioid-induced hyperalgesia and, 85, 88f in multimodal analgesic therapy, 189t withdrawal from, 242 half-life and plasma concentration of, 162t neostigmine use and, 202 Metoclopramide, for nausea and vomiting in postoperative hemostasis and, 174 nerve sheath infusion of, for prevention of Ketorolac, for arthroscopic procedures, 167, 168 children, 216 for cesarean section analgesia, 234, 234f phantom and stump pain, 51 mGluR receptors, in nociception, 72 for pain relief in thoracotomy, 163-164 Lower extremity, outpatient surgery on, Midazolam, for pain relief, 201t, 203 for postlaparoscopic gynecological surgical Mind-body therapies, for pain relief, 190, 200 255-256, 256f, 257f Misoprostol, as prostaglandin replacement pain, 164, 165t Lumbar epidural block, in children, 213-214 gastrointestinal bleeding with, 171 Lung dysfunction, postoperative, 157-158, therapy, 171 half-life and plasma concentration of, 162t Mitogen-activated protein (MAP) kinases, 32 in children, 212 158f. See also Respiratory depression. MK-801, in opioid-induced hyperalgesia, 90, 90f in outpatient surgery, 252t Modulation, of pain, definition of, 34 postoperative hemostasis and, 174 M prostaglandin synthesis and, 162 mechanisms of, 36-38, 36f-38f, 72 vs. opioids, 176 Macrophages, in inflammatory response, 30, 31f Molecular mimicry, 48 in neuroimmune system modulation, 47 Moore, phases of in response to surgery, 27 acute renal failure risk and, 170 Morphine. See also Opioids. Kidney function, in elderly, 219, 220t, 221 Magnesium, in preemptive analgesia, 115 Marijuana, dependence on, 242-243 administration of, intrathecal, 142 nonsteroidal anti-inflammatory drug use Mast cell(s), degranulation of, in pain intravenous, 137-138, 138b, 140t and, 170, 170b, 190, 221 spinal, 132 transduction, 34 transdermal, 199-200 opioid pharmacokinetics and, 130 in inflammatory response, 30 Kinases, extracellular signal-related, 32 Mastectomy, pain following, causes and risk epidural, for cesarean delivery, 226t for postoperative cesarean section intracellular, in pain transduction, 45f factors for, 50, 260 analgesia, 225, 226f Kinins, nociceptive pain and, 37-38 Matrix metalloproteinases, in inflammatory vs. systemic opioids, 75-76, 76t Knee arthroscopy, outpatient surgery on, response, 30 for cesarean delivery, 226t, 228t 255-256, 256f McGill Pain Questionnaire, 104, 105f for neuropathic pain, 57t for postoperative cesarean section analgesia, L short form of, 104, 106f MDMA (Ecstasy), 242 225, 226f, 227, 228, 229f, 230f Lamina(ae), in pain transmission, 34-35 Medical negligence, definition of, 15b for spinal analgesic effect, 141-142, 142t Lamotrigine, for neuropathic pain, 54t Medicine, evidence-based, components of, 1 in opioid-tolerant patients, 246 Language bias, 2 in outpatient surgery, 253, 253t Laparoscopic cholecystectomy, chronic pain definition of, 1 in patient-controlled analgesia, 231, general-purpose sources for, 9t with, 261 guideline development and, 15, 16b, 17, 232t, 233 multimodal analgesic therapy for, 187 dosage for, 149t, 226, 226f nonsteroidal anti-inflammatory drugs with, 17b, 18, 18b, 18t, 19t in children, 213, 213t guideline use and, 15 pharmacokinetics of, 149t 165, 165b, 166t practice of, 4 in studies of preventive analgesia, 113, 114f outpatient, 254 principles of, 1-4 intrathecal, administration of, 142 port site pain with, 51 search for evidence in, 1-2 for cesarean delivery, 228t Laparoscopy, chronic pain with, 261 MEDLINE, in search for evidence, 1-2 for postoperative cesarean section gynecological, nonsteroidal anti-inflammatory in search for outcome studies in multimodal analgesia, 228, 229f, 230f drug use with, 164-165, 165t analgesic therapy, 187-188, 193t intravenous, 137-138, 138b, 140t Lateral femoral cutaneous nerve block, in Melanocortin-1 receptor, 68 ketamine use with, 203 Meloxicam, cardiovascular toxicity and, 172 metabolites of, 129 children, 215 Membrane depolarization, B2 receptor nefopam use with, 203 Leukocytes, in inflammatory response, 31 oral, 139, 140t Levobupivacaine, with clonidine, in brachial activation and, 38 parenteral, in ambulatory surgery patients, Men, opioid pharmacokinetics in, 130 plexus block in children, 214 138-139 Lidocaine, epidural, in preemptive pain in, vs. pain in women, 68 pharmacokinetics of, 129t, 149t Mendelian genetics, 63 polymorphisms of μ opioid receptor and, 67 analgesia, 112f Meperidine (pethidine), epidural, 226t spinal, 132, 141-142, 142t in brachial plexus block in children, 214 transdermal, 199-200 in preemptive multimodal analgesia, 188 for cesarean section analgesia, 226t, 227 with fentanyl or sufentanil, for cesarean Lignocaine, for pain relief, 201t, 203-204 in outpatient surgery, 253, 253t for prevention of complex regional pain in patient-controlled analgesia, 231, 232t, 233 section analgesia, 226t, 227 Morphine-3-glucuronide, analgesic syndrome, 52 dosing guidelines for, 149t Limbic system, 35 pharmacokinetics of, 149t efficacy of, 130 Lipid solubility, of opioids, 128. See also in patient-controlled epidural analgesia, for Morphine-6-glucuronide, analgesic Opioids, lipophilic. cesarean section pain, 225, 227 efficacy of, 129 Lissauer’s tract, 34 intrathecal, for cesarean section delivery and μ-opioid receptor polymorphism and, 67 Liver function, in elderly, 219, 220t μ-opioid receptors. See Opioid receptors, μ. postoperative analgesia, 228t, 229 Music, for pain relief, 200 opioid pharmacokinetics and, 129, intravenous, 138, 138b, 140t 129t, 130 metabolites of, 130 oral, 139, 140t

Index 271 Mutation, definition of, 63 Nerve sheath, local anesthetic infusion of, for Nitric oxide synthetase, B2 receptor activation Myocardial infarction, postoperative, local prevention of phantom and stump pain, 51 and, 38 anesthetic–based analgesia and, 79, 80f Nerve stimulator, for positioning infraclavicular NMDA receptor antagonists, 47 catheter, 255 in alcohol withdrawal, 241, 243 N in opioid abuse, 243 in nerve blockade in children, 214, 215 in opioid-induced hyperalgesia, animal Nalbuphine, addiction to, postoperative Nervous system, changes in after injury, 259-260 studies of, 89-91, 89f, 90f recovery program for, 247 Neurapraxic injury, 50 human studies of, 91-92, 91f Neuraxial blockade. See also Opioids, neuraxial. in preemptive analgesia, 115 for cesarean section analgesia, 234f, 235 ketamine as, 202 for pruritus in children, 216 central, postoperative pulmonary in cesarean section analgesia, with complications and, 159 NMDA receptor system, in central sensitization, 36, 37f, 38f, 47 hydromorphone, 227 morbidity and mortality with, 77, 77f, 78f Nalmefene, for alcohol abuse, 243 vs. general anesthesia, 155 in nociceptive pain, 38, 72 Naloxone, for opioid-induced respiratory phosphorylation and activation of, with Neurohumoral reflex arc, 27 depression, 133, 143, 216 Neurohumoral response, nociceptor sensitivity opioid binding, 85 Naltrexone, addiction to, postoperative N-methyl-D-aspartate (NMDA) receptors. and, 34, 35f recovery program for, 247 to surgery, 27, 28t, 29-30, 29f, 29t See NMDA receptor antagonists; NMDA for alcohol dependence, 241, 243 Neuroimmune system, modulation of, 47-48 receptor system. Naproxen, cardiovascular toxicity and, Neurokinin receptors (NK-1), in central Nociception, 127 neurobiology of, 72, 72f, 84 171-172 sensitization, 36 opioid drug use and, 84 for arthroscopic procedures, 167 in nociception, 72 Nociceptive pain, 41, 41f for obstetrical pain, 166 Neuroma, in stump pain, 51 agonists and antagonists of, 37-38 for postlaparoscopic gynecological surgical Neuron(s), afferent, nociceptors of, 34, 35f characteristics of, 34, 35t dorsal horn, in neuropathic pain, 46f, 47-48 definition of, 34 pain, 164 mechanisms of, 34-38, 46t half-life and plasma concentration of, 162t in pain, 46f modulation of, 36-37, 36f, 37f, 38, 38f, 72 in outpatient surgery, 252t dorsal root ganglion, axonal injury and, 38 opioids for, 137 Nausea and vomiting, in children, 216 ectopic excitability of, 44, 47 perception of, 35 serotonin-3-receptor antagonists for, 66 nociceptive-specific, 34, 36f processing of, 183t with opioid administration, 134, 139, noradrenergic, in modulation of pain, 36 transduction of, 34, 35f phenotypic switching of, 44, 45f by B2 receptor, 38 230-231 primary sensory, in pain, 45f transmission of, 34-35, 35f, 36f, 46f with patient-controlled analgesia, 151 serotonergic, in modulation of pain, 36 Nociceptors, A-δ, 34 Nefopam, for pain relief, 201t, 203 spinothalamic tract, 35 C, 34 Negligence, medical, 15b wide dynamic range, 34, 36f in central sensitization, 36, 37f, 38f Neonates, epidural analgesia in, 214 Neuropathic pain, 41f. See also Chronic pain. definition of, 34 maternal systemic opioids and, with anesthetists’s role in, 48-50, 49b, 49t peripheral terminal of, 45f chronicity of, 40 sensitivity of to surgical trauma, 34 intravenous patient-controlled definition of, 40 sensitization of, central, 36, 37f, 38f. analgesia, 233, 233f diagnosis of, 48-49 opioid pharmacokinetics in, 130 distribution of lesions in, 42f See also Sensitization, central. pain processing in, 211-212 etiology of, 40, 43b mechanisms of, 36, 36f Neospinothalamic pathway, 34-35, 36f genes influencing, 63 peripheral, 41-42, 44, 45f. Neostigmine, epidural, for cesarean section mechanisms of, 40-42, 43f-46f, 44, 46t, analgesia, 227 See also Sensitization, peripheral. for pain relief, 201t, 202 47-48, 259-260 “sleeping,” 34 in brachial plexus blockade, as adjunctive opioids for, 137 stimulation of, 34, 35f drug, 156, 156t peripheral, 40, 42f, 44f Nonpharmacologic techniques, in children, 216 intrathecal, for cesarean section analgesia, 229 physical examination for, 49 in outpatient surgery, 253 Nerve blockade, brachial plexus, adenosine postoperative, management of, 53, 53t-57t, 58 Nonsteroidal anti-inflammatory drugs, clinical with, 200 clonidine and neostigmine with, 156, 156t recognized syndromes of, 50-53 efficacy of, 162-169, 176 in children, 214 causes of, 43b cytochrome P450 polymorphisms and, 68 opioids with, 155 general properties of, 162, 162t continuous, devices used for, 250, 252f, 254 prevalence of, 40 in arthroplasty, 168-169, 169t fascia iliaca compartment, in children, 215 prevention of, 49-50, 49b, 49t in arthroscopy, 167-168, 168t femoral nerve, in children, 214-215 processing of, 183t in cesarean section analgesia, 166, 167t, for prevention of pain hypersensitivity, 72, 73f risk assessment of, 49, 49b, 49t iliohypogastric, in children, 216 symptoms of, 49 233-235, 234f ilioinguinal, in children, 216 vasculitic, 48 in children, 212 interscalene, in children, 214 Neurotmesis, 50 in elderly, 221-222 in outpatient surgery, 254 Neurotoxicity, spinal cord, μ-opioid receptor in gynecological laparoscopic surgery, lateral femoral cutaneous, in children, 215 penile, in children, 215-216 binding and, 84 164-165, 164b, 165t peripheral, adjunctive drugs with, 155-156, Neurotransmitter(s), G protein-signaling in laparoscopic cholecystectomy, 165, 156t, 157t in children, 214-216 systems and, 38 165b, 166t in elderly, 223 in dorsal horn, in central sensitization, 47 in multimodal analgesic therapy, 189, opioids used with, 144, 144t in nociception, 38, 72 popliteal fossa, in children, 215 inhibitory, in neuropathic pain, 48 189t, 190b regional, intraoperative, in children, 216 Neurotrophic factor, brain-derived, in in nonlaparoscopic gynecological surgery, suprascapular, in outpatient surgery, 254 three-in-one, in children, 214-215 peripheral nerve injury, 44 165-166, 166b Nerve growth factor, in nociceptive pain, 38 Neutrophil-derived elastase, in inflammatory in obstetrical procedures, 166-167, 166b, 167t in peripheral sensitization, 44, 45f in opioid-tolerant patients, 246 Nerve injury, iatrogenic, prevention of, 49-50 response, 30 in orthopedic surgery, 167-169, 167b, types of, 50 Neutrophils, in inflammatory response, 30, 31f 168t, 169t in neuroimmune system modulation, 47 in outpatient surgery, 252-253, 252t New Zealand, use of guidelines in, 14b in preemptive analgesia, 114-115 Nimesulide, 164 in spinal surgery, 168, 169t Nitric oxide, in central sensitization, 37 in thoracic surgery, 162-164, 163b, 163t in inflammatory response, 30 in neuroimmune system modulation, 47

272 Index Nonsteroidal anti-inflammatory drugs Opioid receptors, μ (Continued) Opioids, intrathecal administration of (Continued) desensitization of, 84 (Continued) endocytosis of from surface of neuronal mechanism of action of, 161-162 cells, 84 for cesarean delivery, 228t opioid-sparing properties of, 162-163, 162f in endogenous opioid system, 127 for postoperative cesarean section NMDA receptor system and, 38 in thoracotomy, 163-164, 163b, 163t opioid binding to, 84-85 analgesia, 228-231, 229f, 230f pharmacology of, 161-162 polymorphisms and mutations of, 67 perioperative use of, 140t, 142-143, potentiation of, 163 respiratory depression and, 133 short-term vs. long-term use of, 190 subtypes of, 67, 128 143b, 143t systemic, 74-75 intravenous, 137-139, 138b, 140t toxicity of, 170-175 Opioids, addiction to, 241, 242, 243-244 lipophilic, 128 opioid tolerance and, 241, 244, 245, 246 bleeding and, 173-174, 174b perioperative treatment plan for, 244-247 for postoperative cesarean section bone growth inhibition and, 175, 175b postoperative recovery program for, 247 analgesia, 228-229, 229f cardiovascular, 171-173, 171b, 173b, 173t gastrointestinal, 170-171, 171b administration of, buccal-transmucosal, 131 intrathecal administration and, 142 renal, 170, 170b epidural, 132, 141t, 142 short-acting, in cesarean section analgesia, Noradrenergic neurons, in modulation intra-articular, 144, 145b of pain, 36 intramuscular, 131 226-227, 227f Norepinephrine, in modulation of pain, 36 intranasal, 132 spinal administration of, 132, 141, in stress response, 27, 29t intrathecal, 132, 142, 228-231, 229f, 230f Nortriptyline, for neuropathic pain, 56t intravenous, 137-139, 138b, 140t 141t, 142 NSAIDs. See Nonsteroidal anti-inflammatory oral, 131 with morphine, 227 drugs. postoperative, 131-132. See also Opioids, mechanism of action of, 127-128, 128t Nuclear factor κB, 30 perioperative use of. metabolites of, 129-130, 129t Nucleus raphe magnus, 35 routes of, 131-132 neuraxial, advantages of, 225b Nucleus reticularis giganticocellularis, 35 spinal, 132, 141t, 143 adverse effects of, 230-231 Number-needed-to-harm, for bleeding risk transdermal, 131, 199-200 for cesarean delivery, with postoperative with NSAIDs, 174 in opioid-tolerant patients, 246 for intrathecal opioid-induced respiratory patient-controlled analgesia, 233 adverse effects of, 132-134 patient outcomes and, 75-76, 76t depression, 21 antihyperalgesic drugs and, fixed-dose and pruritus with, 133 for opioids, 137 urinary retention with, 134 Number-needed-to-treat values, for analgesics, flexible-dose combinations of, 186, 186t vs. general anesthesia, 155 as adjuncts in peripheral nerve blockade, 155 vs. local anesthetic–based analgesia, 75 191, 191f classification of, 128, 128t vs. systemic opioids, 75-76, 76t for opioids, 137 combinations of, in cesarean section nonsteroidal anti-inflammatory drug action Numerical rating pain scales, 103, 103f in elderly, 221 analgesia, 227, 229-230 and, 162-163, 162f Nurse(s), specialist, in acute pain services, in compound preparations, 139-141, 141t in opioid-tolerant patients, 246 dependence on, 239-240 oral, administration of, 131 120-122, 121t, 123 pharmacological considerations with, 242 controlled-release preparations of, 139 detoxification from, 247 for analgesia in children, 213 O endogenous system of, 127 immediate-release preparations of, epidural, administration of, 132, 141t, 142 Obesity, as risk factor for limb amputation, 260 139, 140t opioid pharmacokinetics and, 130-131 delayed gastric emptying with, 133 in opioid-tolerant patients, 246 after cesarean section, 225-227 perioperative use of, 139-141, 139b, Observational studies, vs. randomized benefits of, 141-142 controlled trials, 2 choice of, 141-142, 141t 140t, 141t for cesarean delivery, 226t parenteral, in ambulatory surgery patients, with control groups, 6, 6f in elderly, 223, 223t Obstetrical procedures. See also Cesarean section. local anesthetics combined with, 142, 142t 138-139 perioperative use of, 140t, 141-142, 141b, perineuronal, 144, 144t nonsteroidal anti-inflammatory drug use perioperative use of, 137-145 with, 166-167, 166b, 167t, 174 142t, 143t suggested regimens for, 142t epidural, 140t, 141-142, 141b, 142t, O-Desmethyltramadol, affinity of for μ-opioid vs. systemic opioids, 75-76, 76t 143t. See also Opioids, epidural. receptors, 66 excitatory effects of, 84-92 for neuropathic pain, 57t, 58 for neuropathic pain, 137 Older adults. See Elderly. for patient-controlled analgesia, 231, for peripherally mediated analgesia, 144, Omeprazole, gastrointestinal effects of, 171 Oncogenes, in central sensitization, 37, 37f 232t, 233 144t, 145b Ondansetron, CYP2D6 genes and, 66 hydrophilic, 75 intrathecal, 140t, 142-143, 143b, 143t. for nausea and vomiting in children, 216 analgesic benefits of, 141, 141t See also Opioids, intrathecal. for neuraxial opioid-induced pruritus, 133 intrathecal administration of, 132, 142 intravenous, 137-139, 138b, 140t for pain relief, 201t, 205 local anesthetics combined with, 142, 142t methodology used for, 137 Opioid receptors, 67 spinal administration of, 132 oral, 139-141, 139b, 140t. central and peripheral localization of, hyperalgesia induced by, 85, 86f-89f, 89 mechanisms of, 84-85, 85b See also Opioids, oral. 127-128 modulation of, 89-92, 89f-92f spinal, 132, 140t, 141-143, 141b, 141t, δ, activation of, 128, 128t in elderly, dose reduction in, 221 epidural administration of, 223, 223t 142t, 143b, 143t, 144b. in endogenous opioid system, 127 in multimodal analgesic therapy, See also Opioids, epidural; Opioids, NMDA receptor system and, 38 intrathecal. in modulation of nociceptive pain, 36, 38, 47 187-188, 189t pharmacodynamics of, in patient-controlled κ, in endogenous opioid system, 127, in outpatient surgery, 253, 253t analgesia, 148 in preemptive multimodal analgesic therapy, pharmacokinetics of, 128-131, 129t 128, 128t factors influencing, 130-131 in males and females, 68 114, 188 in patient-controlled analgesia, 148, 149t NMDA receptor system and, 38 intra-articular, 144, 145b pharmacology of, 127-134 μ, activation of, 128, 128t intrathecal, administration of, 132, 142, physicochemical characteristics of, 128, 129t side effects of, 74 adverse effects and, 133 228-231, 229f, 230f spinal administration of, 132, 141, 141t, 142 affinity of O-desmethyltramadol for, 66 respiratory depression and, 143, 143b, 144b alternative splicing of, 67 systemic, for prevention of central antagonists of, for alcohol abuse, 243 sensitization, 110 in children, 213 for opioid abuse, 243 patient outcomes and, 74, 75-76, 75f, 76t tolerance and. See Tolerance, opioid-induced.

Index 273 Opioids (Continued) Pain (Continued) Pain, preoperative (Continued) transdermal administration of, 131, 199-200 central sensitization and. See Sensitization, patient education about, 96. in opioid-tolerant patients, 246 central. See also Patient education. withdrawal from, 242 chronic. See Chronic pain; Neuropathic pain. prediction of postoperative pain and, 52, current, future pain and, 110 104, 107, 110 Opioid-sparing effect, of nonsteroidal deafferentation, in phantom pain, 51, 259 preoperative intervention for, 96 anti-inflammatory drugs, 162-163, 162f definition of, 34, 95, 137 descending inhibitory pathways of, 36-37, prevention of, targets of, 109-110, 110f in thoracotomy, 163-164, 163b, 163t 36f-38f randomized controlled trials of, assessment Orchidectomy, outpatient, 254 developmental, 211-212 Orchiopexy, outpatient, 254 disinhibition of, 46f, 48, 128 of, 2-3, 6-8 ORL-1, in endogenous opioid system, 38, 127 functional, 41f, 46t registry of, 191 Orphanin-FQ, 127 gender differences in, 68 vs. observational studies of, 2 Orphenadrine, for pain relief, 201t, 204 genetic influences on, 63-69 referred, 37 Orthopedic procedures. See also specific hyperalgesia and. See Hyperalgesia. sources of, 102 in children, 211-216. See also Children. stump. See also Phantom pain. procedures, e.g., Arthroplasty. in opioid-tolerant patients, 241, 245-247. causes and risk factors for, 51, 260 complex regional pain syndrome and, See also Tolerance, opioid-induced. sympathetic nervous activation and, integration of at higher centers, 35, 259-260 52b, 263 management of, acute, 80-81. See also Acute 27, 29f, 71 neostigmine in, 202 pain services. team approach to, 121, 121t nonsteroidal anti-inflammatory drug use institutional commitment to, 97-98, 98f transduction of, 34, 38 national agenda for, 98 transmission of, 34-35, 46f with, 167-169, 167b, 168t, 169t objectives for, 95-98, 95t types of, 41f, 183t bleeding risk and, 174 rationale for, 95-96 undertreatment of, 95, 96, 102, 118, Osmolarity, in stress response, 30 mechanisms of, 34-38, 40-42, 43f-46f, 44, Osteoarthritis, multimodal analgesic therapy 46t, 47-48, 259-260 186, 187f for, 187 pain states associated with, 46t chronic pain and, 191 Outcomes (patient). See Patient outcomes. multimodal therapy for. See Analgesia, in opioid-tolerant patients, 244, 245-246 Outpatient surgery, postoperative pain multimodal. variability in, 63, 64f management in, 249-257 neurohumoral response to, 27-30, 28t, Web-based guidelines on, 124 in abdominal surgery, 253-254 29f, 29t Pain pathways, analgesia and, 183f in ear, nose, and throat procedures, 254 nociceptor sensitivity and, 34, 35f central, ascending, 34-35, 35f, 36f in gynecological surgery, 254 neuropathic. See Chronic pain; Neuropathic descending inhibitory, 36-37, 36f-38f in lower extremity surgery, 255-256, pain. perinatal, 211-212 nociceptive. See Nociceptive pain. Pain Rating Index, on McGill Pain 256f, 257f patient outcomes and, 71-81. See also Patient Questionnaire, 104 in plastic surgery, 254 outcomes. Pain scales, categorical, 103 in upper extremity surgery, 254-255, 255f perception of, 34, 35 in children, 212 in urological surgery, 254 in elderly, 219 in elderly, 220, 221 principles of, 249-253 nitric oxide and, 30 numerical rating, 103, 103f, 221 Oxcarbazepine, for neuropathic pain, 54t peripheral, modulation of, 36-37, 36f-38f picture, 103-104, 104f Oxford Bandolier website, 10 neuropathic, 40, 42f, 44f usefulness of, 102 Oxycodone, for neuropathic pain, 57t perception of, 35 verbal descriptive, 103 in multimodal analgesic therapy, 187 transduction of, 34, 35f verbal rating, 103 in opioid-tolerant patients, 246 transmission of, 34-35, 35f, 36f visual analogue, 103, 103f in outpatient surgery, 253, 253t persistent, in central sensitization, 36, 37. in elderly, 220f in patient-controlled analgesia, dosing See also Sensitization, central. in opioid-tolerant patient, 245 phantom, causes and risk factors for, 51, in thoracotomy, 163 guidelines for, 149t 51t, 260, 261, 261t, 262 Pain score, documentation of, 120 pharmacokinetics of, 149t postcholecystectomy, 51-52, 261 Paleospinoreticulodiencephalic pathway, oral, 139, 140t, 141t in outpatient surgery, 254 34-35, 36f pharmacokinetics of, 129t, 149t multimodal analgesic therapy for, 187 Pancreatic hormones, in stress response, 29t, 30 plus acetaminophen, 141t nonsteroidal anti-inflammatory drug use Paracetamol, in elderly, 221 Oxymorphone, in patient-controlled with, 165, 165b, 166 Parecoxib, cardiovascular toxicity and, 172, 173t analgesia, 231 post-inguinal hernia repair, causes and risk for postlaparoscopic gynecological surgical factors for, 50-51, 261 P in outpatients, 254 pain, 165 postmastectomy, causes and risk factors for, in outpatient surgery, 253, 253t p38 MAP kinase, 32 50, 260 with opioids, for gynecological surgical pain, in peripheral nerve injury, 44 post-thoracotomy, 50, 260, 261 prediction and prevention of, 109-115 166, 166b Pain. See also specific types of pain, e.g., preemptive analgesia for, 72, 72f, 73f, Parent’s Postoperative Pain Measure, 212 Nociceptive pain. 74, 96 Patient(s), dissatisfaction of, with controversy in, 110-113, 111f-113f acute, 71. See also Acute pain services. definition of, 110-111 undertreatment for pain, 186 guidelines for, 21-22 history of, 110 opioid-tolerant, education of, 245 in outpatient surgery, 250 pain scales and, 102, 103-104 afferent transmission of, general anesthesia multimodal, 188 selection of, for patient-controlled analgesia, and, 27, 110 timing of, evidence-based reviews of, 113-115, 114t 150, 150b in inflammatory response, 30 studies of, 111-112, 111f, 112f Patient education, chronic pain and, 261 to dorsal horn, 34, 35f preoperative, in opioid-tolerant patients, ascending pathways of, 34-35, 35f, 36f 244-245 in outpatient surgery, 249, 250f assessment of, behavioral scales in, 102 on opioid tolerance, 245 in elderly, 220-221, 220b on pain control, acute pain service in infants and children, 212 measurement of, 103-107 implementation and, 120 multidimensional tools for, 104, 105f, on patient-controlled analgesia, 150 preoperative, 96 106f, 107, 107f Patient outcomes, acute pain service patient’s self-report in, 102 physical examination in, 102 implementation and, 119-120 summary measures of, 107 benefits of and harm from, time intervals for, 102 unidimensional tools for, 103-104 guidelines on, 13

274 Index Patient outcomes (Continued) Phosphorylation, in peripheral sensitization, Psychoneuroimmunologic responses, in effect of different analgesic regimens on, 44, 45f chronic pain, 260 74-79 postoperative pain and, 71-81 of NMDA receptor, in central sensitization, 47 in stress response, 30 research on, bias and, 2 with opioid binding, 85 Psychosocial factors, chronic pain and, 260 Public Health services, guideline Patient-controlled analgesia, 148-152 Picture pain scales, 103-104, 104f background infusion in, 149-150, 149t, Piroxicam, for pain in thoracotomy, 164 development by, 12 231, 233 Publication bias, 2, 191 basic principles of, 148-149, 149t intra-articular, for arthroscopic Pulmonary complications, local deaths associated with, 152 procedures, 168 device used for, 74, 75f anesthetic–based analgesia and, 77-78, 78f dosing of, 149-150, 149t, 150t Pituitary hormones, in stress response, 29, 29t regional anesthesia and, 157-159, 158f efficacy of, 74, 75f, 150-151 Placebo effects, in pain trials, 7 Pump, programmable infusion, for ambulatory hazards of, 152, 152b Plasma protein binding, in opioid in cesarean section, 231-233, 232t, 233f continuous nerve blocks, 250, 252f in children, 213, 213t pharmacokinetics, 131 in elderly, 222, 222t Plastic surgery, outpatient, 254 Q in measurement of pain, 107 Polymorphism(s), genetic, definition of, 63 in opioid-tolerant patients, 246 Quantitative sensory testing, in pain intravenous, basal background infusion for, drug effect alterations and, 64-65 assessment, 104, 107, 107f 231, 233 drug interactions and, 66-67 for cesarean section analgesia, 226, 226f, single-nucleotide, 63 Quantitative sudomotor axon reflex response, 231-233 Polymorphonuclear cell(s), in stress response, 30 in neuropathic pain, 49 opioid selection for, 231, 232t, 233 Polypharmacy, in elderly, 221 safety of, 233, 233f multimodal analgesia and, 183-184 R troubleshooting problems with, 231, 232t Poor metabolizers, 65, 66, 130 vs. epidural patient-controlled Popliteal fossa nerve block, in children, 215 Racial groups, variation in drug-metabolizing analgesia, 231 Population, of randomized controlled trial, capacity in, 65, 66t with neuraxial opioids for cesarean delivery, 233 external validity of, 8 RAND Corporation, studies of, 12 lockout interval in, 149, 149t, 150t intention-to-treat analysis of, 8 Random allocation, bias and, 2 management of, 150, 150b Postoperative nausea and vomiting, monitoring of, 150 in children, 216 concealment of, 7 morphine with, after cesarean section, serotonin-3-receptor antagonists for, 66 in assessment of randomized controlled 226, 226f with opioid use, 134, 139, 230-231 patient satisfaction with, 151 with patient-controlled analgesia, 151 trials, 6, 7 pump replacement in, 152, 152b Post-thoracotomy pain, analgesic drug in hierarchy of evidence, 6, 6f route of administration in, 148-149 combinations for, 186, 186t Randomized controlled trials, as evidence, 6, 6f safety of, 151, 233, 233f causes and risk factors for, 50, 259, 260, 261 assessment of, 2-3, 6, 7 staff education for, 150 nonsteroidal anti-inflammatory drug use for, critical appraisal of, 6-8 tolerability of, 151 registry of, 191 163-164, 163b, 163t vs. observational studies, 2 Patient-controlled epidural analgesia, clonidine Practice policies, 12, 12b, 13b Ranitidine, gastrointestinal effects of, 171 with, 227 Preoperative pain, in opioid-tolerant patients, Raphe magnus, in modulation of pain, 36 Reactive oxygen species, in inflammatory for cesarean section pain, 225, 227-228, 228t 244-245 in children, 214 patient education about, 96. See also Patient response, 30 local anesthetic with, 76-78, 77f in neuroimmune system modulation, 47 meperidine with, 225 education. in stress response, 30 Peltier probes, 104 prediction of postoperative pain and, 52, Receptor(s), AMPA (alpha-amino-3-hydroxy- Penile nerve block, in children, 215-216 Per protocol analysis, in randomized controlled 104, 107, 110 5-methyl-isoxazole-4-propionic acid), preoperative intervention for, 96 34, 72 trials, 8 Present Pain Intensity Index, on McGill Pain B1 and B2, bradykinin-induced pain and, Periaqueductal gray, 35, 36, 36f Perioperative period, phases of, pain Questionnaire, 104 37, 38 Pressure release devices, for ambulatory in peripheral sensitization, 44 management in, 109, 110f CB-1, in addiction, 244 Peripheral nerve block, in children, 214-216 continuous nerve blocks, 250, 252f excitatory amino acid, 72 PROSPECT Web site, 124 melanocortin-1, 68 in elderly, 223 Prostaglandin E2, hyperalgesia and, 161 mGluR, 72 Peripheral pain, modulation of, 36-37, 36f, neurokinin (NK-1), in central in peripheral sensitization, 36, 42, 43, 45f 37f, 38f Prostaglandins, bone repair and, nonsteroidal sensitization, 36 neuropathic, 40, 42f, 44f in nociception, 72 perception of, 35 anti-inflammatory drug use and, 175, 175b neurotransmitter, G protein-signaling transduction of, 34, 35f coxibs and, cardiovascular toxicity and, 172 transmission of, 34-35, 35f, 36f gastrointestinal function and, nonsteroidal systems and, 38, 128 Peripheral sensitization, 36, 36f, 41-42, 44, 45f NMDA (N-methyl-D-aspartate), antagonists prevention of, 109 anti-inflammatory drug use and, 170, Pethidine. See Meperidine (pethidine). 171, 171b of. See NMDA receptor antagonists. Phantom pain, causes and risk factors for, 51, kidney function and, nonsteroidal in central sensitization, 36, 37f, 38f, 47 anti-inflammatory drug use and, in nociception, 38, 72 51t, 260, 261, 261t, 262 170, 170b phosphorylation and activation of, 38, 85 Pharmacogenetics, 64 nonsteroidal anti-inflammatory drug opioid. See Opioid receptors. Pharmacogenomics, 64 action and, 161, 170-171, 170b, 171b, substance P, 72 Phenytoin, for neuropathic pain, 55t 175, 175b Rectal administration, of opioids, 132 Phosphatidylinositol 3-kinase (PI3-k), 32 Protein C, in coagulation response, 32 Reflex sympathetic dystrophy. See Complex Phospholipase A2, 161 Protein kinase A, in μ-opioid binding, 85 regional pain syndrome. Phospholipase C, B2 receptor in peripheral sensitization, 44, 45f Regional anesthesia, 154-159 Protein kinase C, 32 advantages and disadvantages of, 250, 251b activation and, 38 in peripheral sensitization, 36, 44, 45f in children, 213-214 Protein kinase Cγ, in μ-opioid binding, 85 in elderly, 222-223, 223t Protocols, definitions of, 12, 13b patient outcomes and, 223 Pruritus, in children, 216 in outpatient surgery, 250 neuraxial opioid-induced, 133, 230-231 nonsteroidal anti-inflammatory drug use patient-controlled analgesia and, 151 Psychiatric disorders, in patients with and, bleeding risk and, 174 substance abuse problems, 243

Index 275 Regional anesthesia (Continued) Second messengers, B2 receptor activation Stellate ganglion blockade, complex regional postoperative cognitive dysfunction and, and, 38 pain syndrome and, 52 156-157 postoperative pulmonary complications and, calcium as, 38f Stimulants, dependence on, 242 157-159, 158f in central sensitization, 36-37, 37f Stimulating catheter, in outpatient surgery, prevention of complex regional pain Sedation, with patient-controlled analgesia, 151 syndrome and, 52, 53 Sedatives, dependence on, 242 255, 256 vs. general anesthesia, 154-155, 250, 251b Selection bias, 2 Stress response, glucocorticoids in, 29-30 complex regional pain syndrome and, Sensitivity analysis, in critical appraisal of 52, 53 hypothalamic control in, 27, 29-30, 29t systematic reviews, 9 insulin in, 29t, 30 Registry, of industry-sponsored clinical Sensitization, central, 36-37, 37f, 38f neuroendocrine, acute pain and, 71 trials, 185 neurohumoral, 27, 28t, 29-30, 29f, 29t acute and late phases of, 46f pituitary hormones in, 29 of randomized controlled trials, 191 chronicity of pain and, 84 psychoneuroimmunologic responses in, 30 Rekindling, opioid-induced, 85, 87f, 90, forms of, 47 volume regulation in, 29t, 30 hyperalgesia and, 84 Stretch nerve injury, 49 90f, 91 in deafferentation pain, 51 Study designs, classification of, 18t Relaxation training, for pain relief, 200 in neuropathic pain, 42f, 46f, 47-48, 259 Study types, hierarchy of, 6, 6f, 18b Remifentanil, in ambulatory surgery in thermal injury, 259 Stump pain, causes and risk factors for, 51, 260 mechanisms of, 47 Substance abuse, definitions of, 239-241 patients, 139 postoperative pain and, 72f Substance P, clonidine inhibition of, 230 opioid-induced hyperalgesia and, 85, 88f, prevention of, 109 in central sensitization, 36, 37f, 38f in nociception, 72 89, 89f by preemptive analgesia, 72, 72f, 73f, in pain transduction, 34 clonidine and, 91-92, 91f, 92f 74, 110 in peripheral nerve injury, 44 pharmacokinetics of, 129t Sufentanil, epidural, for cesarean section in obese persons, 130 systemic opioid blockade and, 110 Renal dysfunction, from nonsteroidal of nervous system after injury, 259-260 delivery and postoperative analgesia, anti-inflammatory drugs, 170, 170b, peripheral, 36, 36f, 41-42, 44, 45f 226-227, 226t 190, 221 in ambulatory surgery patients, 139 opioid pharmacokinetics and, 130 prevention of, 109 intrathecal, for cesarean section delivery Renal function, in elderly, 219, 220t Sensory cortex, after injury, 259 nonsteroidal anti-inflammatory drug use Sensory nerve transmission, 34 and postoperative analgesia, 228-229, Sensory neurons, primary, in pain, 45f 228t, 229f and, 221 Serotonergic neurons, in modulation of pain, 36 pharmacokinetics of, 129t Renin, in stress response, 30 Serotonin, 36 Sulindac, half-life and plasma Research. See also Evidence. Serotonin-3-receptor antagonists, 66 concentration of, 162t Sex, opioid pharmacokinetics and, 130 Summed pain-intensity differences access to, 9-10 (SPID), 107 assessment of, 6-9 pain prevalence and, genetic Sunburn, causes of pain with, 259 poor quality of, 5 influences on, 68 Suprascapular nerve block, in outpatient uncertainty of, 5-6 surgery, 254 Reserpine, for prevention of complex regional Sex hormones, in stress response, 29, 29t Surgery, in opioid-tolerant patients, 245 Shoulder, outpatient surgery on, 254 neurohumoral, inflammatory and pain syndrome, 52 coagulation responses to, 27-32 Respiratory depression, acute pain postlaparoscopic pain in, nonsteroidal anti- spinal, nonsteroidal anti-inflammatory drug inflammatory drug use for, 164, 165 use in, 168, 169t service and, 120 thoracic, nonsteroidal anti-inflammatory central neuraxial blockade and, 159 Side effects, of opioids, analgesic efficiency drug use in, 163-164, 163b, 163t in children, 216 and, 74 timing of, complex regional pain syndrome in elderly, 221 and, 52 opioid-induced, 21, 133 of pain relief treatment in children, 216 type of, chronic pain and, 260-261 reduced, in multimodal analgesic Sympathetic nervous system, in stress from neuraxial opioids, 230-231, 231b response, 27, 29f from spinal opioids, 143, 143b, 144b therapy, 191 postoperative pain and, 71 patient-controlled analgesia and, 151 Signal transduction, by B2 receptor, 38 Systematic reviews, critical appraisal of, 8-9 safety of, 233, 233f data resources for, 21t Respiratory problems, postoperative, etiology in inflammatory response, 31-32 in assessment of evidence, 3 of, 157-158, 158f in peripheral nerve injury, 44 of randomized controlled trials, 6, 6f Reticular formation, in central pain ascending Single-nucleotide polymorphisms, 63 vs. meta-analysis, 18 pathway, 35, 36f Smoking, as risk factor for limb Rimonabant, in opioid addiction, 244 T Rofecoxib, 96 amputation, 260 cardiovascular toxicity and, 171b, 172 Sodium channel, axonal injury and, in Tenoxicam, for cesarean section analgesia, for arthroscopic procedures, 167, 190 234f, 235 in multimodal analgesic therapy, 190 nociceptive pain, 38, 47 in outpatient surgery, 253, 253t Na(v)1.8, in peripheral sensitization, 36 for postlaparoscopic gynecological surgical preemptive analgesia and, 115 Somatosensory cortex, in modulation pain, 164 Ropivacaine, with clonidine in brachial plexus block in children, 214 of pain, 36 for post-thoracotomy pain, 164 Rostral ventromedial medulla, descending Somatosensory testing, in quantitative sensory intra-articular, for arthroscopic facilitation of, 85 testing for pain, 104, 107, 107f procedures, 168 S Somatostatin, in nociception, 72 with opioids, for gynecological surgical Specialty organizations, guideline development Safety, of cyclooxygenase inhibitors, 96. pain, 166 See also Cyclooxygenase inhibitors. by, 13b TENS (transcutaneous electrical nerve Spinal anesthesia, in elderly, 222-223, 223t of multimodal analgesia, 183 stimulation), 197, 198f of patient-controlled analgesia, 151, in preemptive analgesia, 113, 113f Tetracaine, in brachial plexus block in vs. general anesthesia, for hip fracture, 233, 233f children, 214 of valdecoxib, 190 154-155 Tetracyclic antidepressants, for pain relief, Sciatic nerve block, in outpatient surgery, 256, Spinal cord, disinhibition in, 46f, 48 201t, 204 256f, 257f dorsal horn of, in neuropathic pain, 46f, 47-48 in nociception, 72 Spinal reflex arcs, postoperative pain and, 71 Spinal surgery, nonsteroidal anti-inflammatory drug use in, 168, 169t Spinothalamic pathway, 34-35, 36f Src-kinases, 32 Standards, definitions of, 12, 12b, 13b

276 Index Thalamus, lateral and medial, in central pain Transcription factors, in central sensitization, V ascending pathway, 35 46f, 47 Valdecoxib, cardiovascular toxicity and, 171b, neuroplasticity in, after injury, 259 Transcutaneous electrical nerve stimulation 172, 173t Thermal injury, to skin, causes of pain with, 259 (TENS), for pain relief, 197, 198f Thermography, for neuropathic pain, 49 in outpatient surgery, 253, 253t Thoracic surgery, nonsteroidal anti- Transdermal administration, of fentanyl, 74 safety of, 190 of opioids, 131, 199-200 Validity, external, of randomized controlled inflammatory drugs in, 163-164, in opioid-tolerant patients, 246 163b, 163t trials, 8 Thoracotomy, analgesic drugs plus Transduction, of pain, by B2 receptor, 38 Valproate, for neuropathic pain, 55t antihyperalgesic drug combinations for, definition of, 34 Vasculitic neuropathy, 48 186, 186t in inflammatory response, 31-32 Vasoactive intestinal polypeptide, in nonsteroidal anti-inflammatory drug use in, in peripheral nerve injury, 44 nociception, 72 163-164, 163b, 163t Transforming growth factor-β, in inflammatory Vasoconstriction, in stress response, 30 pain with, causes and risk factors for, 50, response, 30 Venlafaxine, in studies of preventive analgesia, 259, 260, 261 Transient receptor potential V1 channel 113, 113f Three-in-one nerve block, in children, 214-215 (TRPV1), in peripheral nerve injury, 44, Venous thrombosis, in regional vs. general Thromboembolism, nonsteroidal anti- 45f, 47 anesthesia, 154, 155 inflammatory drugs and, 171-172, 171b in peripheral sensitization, 44, 45f local anesthetic–based analgesia and, 78, 78f Thrombomodulin, in coagulation response, 32 Tricyclic antidepressants, for neuropathic pain, Verbal descriptor scale, in elderly, 221 Thrombotic events, local anesthetic–based Verbal rating/descriptor pain scales, 103 56t, 58 Vibration sense, testing of, 104 analgesia and, 78 for pain relief, 201t, 204 Video-assisted thoracoscopic surgery (VATS), Thromboxane A2, 161 Trimipramine, genetic influences on, 68 Tiagabine, for neuropathic pain, 55t Tropisetron, CYP2D6 genes and, 66 nonsteroidal anti-inflammatory drug use Tissue damage, nociception and, 72 Tubal ligation, pain with, nonsteroidal anti- with, 164 Vioxx, trials of, cardiovascular toxicity and, 172 peripheral sensitization and, 42, 45f inflammatory drug use for, 164, 165 Vioxx Gastrointestinal Outcomes Research Tolerance, cross-tolerance and, 67 Tumor necrosis factor-α, in inflammatory (VIGOR) study, 171, 172 Visual analogue pain scales, 103, 103f definition of, 84, 241 response, 30, 31t in elderly, 220 opioid-induced, 84 in nociceptive pain, 38 in opioid-tolerant patients, 245 in peripheral sensitization, 44 in thoracotomy, 163 analgesic efficacy and, 74 in stress response, 27 Vitamin C, for neuropathic pain, 53 animal studies of, 85, 87f, 88f, 89-91, Tyrosine kinase, in inflammatory response, Volume regulation, in stress response, 29t, 30 Volunteers, bias and, 2 89f, 90f 31-32 Von Frey hairs, 104 definition of, 84 human studies of, 91-92, 91f, 92f U W pain undertreatment and, 246 perioperative treatment plan for, 244-247 U. S. Agency for Health Care Policy and Warfarin, with nonsteroidal anti-inflammatory tapering of dose in, 245-247 Research, 17 drug use, 174 Tonsillectomy, nonsteroidal anti-inflammatory drug use and, 174 practice guidelines of, 21-22 Whole body function, in elderly, 219, 220t Topical drugs, for neuropathic pain, 58, 58t U. S. Agency for Healthcare Research and “Wind-up” phenomenon, 262 Topiramate, for neuropathic pain, 55t Total pain relief (TOTPAR), calculation of, in Quality, 17 in central sensitization, 36, 37f, 38f research pain assessment, 107 practice guidelines of, 21-22, 71 preemptive analgesia and, 96 Tramadol, acetaminophen with, in multimodal U. S. Department of Health and Human Women, opioid pharmacokinetics in, 130 analgesia, 184-185, 185f, 188, 188f pain in, vs. pain in men, 68 as adjunct in plexus nerve blocks, 156, 157t Services, guideline development by, 12 Wound, as organ, in inflammatory response, 30 epidural, in cesarean section analgesia, 227 U. S. Food and Drug Administration mediators derived from, in inflammatory for neuropathic pain, 57t in elderly, 221 (FDA), regulation of combination response, 30-31, 31t intravenous, 138, 138b, 140t therapies by, 185 metamizole and, in multimodal analgesia, U. S. Veterans Health Affairs, Office of Quality and Performance, pain guidelines of, 124 185, 185f Ultrarapid metabolizers, 65, 66 oral, 139, 140t, 141t Ultrasound, for positioning of infraclavicular perineuronal, 144 catheter, 255, 255f pharmacokinetics of, in patient-controlled United States, use of guidelines in, 14b, 15 Upper extremity, outpatient surgery on, analgesia, 149t 254-255, 255f variation in drug-metabolizing capacity Urinary effects, of opioids, 134 Urinary retention, with patient-controlled and, 66 analgesia, 151 Urological surgery, outpatient, 254