Perioperative Management of Acute Pain in the Opioid-dependent Patient
2004; Lippincott Williams & Wilkins; Volume: 101; Issue: 1 Linguagem: Inglês
10.1097/00000542-200407000-00032
ISSN1528-1175
AutoresSukanya Mitra, Raymond S. Sinatra, David C. Warltier,
Tópico(s)Opioid Use Disorder Treatment
ResumoPAIN is “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”1In settings where pain is poorly controlled, patients suffer needlessly and may develop untoward emotional and cognitive responses that negatively affect behavior, rehabilitation, and quality of life. Providing rapid and effective relief of pain remains a humanitarian issue, whereas allowing patients to suffer as a result of analgesic undermedication may be considered a breach of fundamental human rights.2–4Noticeable shifts in attitude have occurred in recent years regarding the use of opioids for the treatment of benign and malignancy-related pain. Primary care physicians and pain specialists prescribe opioids to a greater number of patients and in doses appropriate to needs.3–7A variety of opioid analgesics and delivery systems have been introduced that have increased patient satisfaction, physician acceptance, and overall use. Concomitant with improvements in pain relief and quality of life, an increasing number of patients are affected by issues related to opioid tolerance and physical dependence. There have been only a small number of published reviews that address the treatment of acute pain in patients with substance abuse disorders,3–5and fewer have focused specifically on perioperative pain management in opioid-dependent patients.6,7This review outlines factors responsible for opioid tolerance, physical dependence, and addiction and provides perioperative analgesic dosing guidelines for this specialized subset of patients.Many patients who present for surgery and anesthesia may be opioid dependent or at least moderately tolerant to the therapeutic effects of opioid analgesics.5–7Causal factors underlying dependency include substance use disorder and, more commonly, legitimate use of opioid analgesics for treatment of chronic benign pain or malignancy-associated pain. Perioperative management of opioid-dependent patients poses a special challenge to primary caregivers, anesthesiologists, and pain specialists alike. This problem emanates from the often-conflicting needs to balance the rights of the patient on one hand and concerns of safety, diversion, and abuse on the other,6,7thus raising important ethical issues.6–9The percentage of patients to whom opioid analgesics for chronic pain are prescribed has increased dramatically in recent years. An Australian study found that in 83% of patients with chronic pain, including back pain, other forms of benign pain, and cancer pain, opioids were prescribed by the patients’ general practitioners at the time of referral to a multidisciplinary pain center.10Moreover, 47% of these patients were treated with strong opioids, such as morphine, oxycodone, and methadone. In another study, long-term opioid use and dose escalation was noted in one third of patients with chronic noncancer pain.11Factors responsible for the increased acceptance and prescription of opioid analgesics include physician education, concerns of analgesic undermedication and inadequate pain control, the favorable side effect profiles of newer semisynthetic and sustained-release opioids, and morbidity associated with nonsteroidal antiinflammatory drugs.3,4,10Opioid-dependent patients, particularly substance abusers, may present with organ damage, infectious diseases such as human immunodeficiency virus, tuberculosis, hepatitis, associated psychological disorders, and drug-specific adaptations such as tolerance, physical dependence, and withdrawal.5,12These variables alone or in combination may diminish opioid analgesic effectiveness in the perioperative setting. The following issues should be considered to provide a comprehensive pain management strategy: (1) key concepts and definitions including substance abuse, physical versus psychological dependence, and tolerance development; (2) clinical differentiation of opioid dependency; (3) preoperative assessment issues; and (4) postoperative management issues.Substance use disorders have been classified according to clinical manifestations of psychological dependence with physical dependence or tolerance or both. Specific definitions can be found in table 113and table 2.13,14It may be noted that the terms and their distinctive boundaries are not always clear, especially terms such as addiction , dependence , abuse , and substance abuse . This is partly because these terms have evolved over time in varying historical and sociocultural contexts.12,13,15They also reflect conflicts regarding appropriate terminology for the complex medical and psychosocial issues that underlie chronic and compulsive substance-using behavior. For example, the strict medical or biologic viewpoint that characterizes substance use disorder essentially as a disease or a disorder conflicts with the strictly sociocultural viewpoint that tends to “demedicalize” such behavior and explain it from a social and cultural context.14–16For the purpose of this review, the terms addiction , substance use disorder , and psychological dependence will often be used interchangeably.The term physical dependence describes alterations in physiologic response that result from opioid binding and receptor-mediated activity.15,16Abrupt discontinuation of oral or parenterally administered opioids leads to opioid withdrawal or abstinence syndrome. This syndrome is characterized by increased sympathetic and parasympathetic responses mediated via the myenteric plexus, brainstem vagal and hypothalamic nuclei, resulting in hypertension, tachycardia, diaphoresis, abdominal cramping, and diarrhea, as well as physiologic and behavioral responses such as shaking (“wet dog shakes”), yawning, and leg jerking (“kicking the habit”).15–18Opioid-dependent patients use the term “cold turkey” to describe the appearance of their cold, pale, goose-bumped skin when opioids are acutely discontinued.14,16These symptoms, although very unpleasant, are rarely life threatening; however, they can often confuse clinical diagnosis and care.17The time course of withdrawal is variable, depending on the opioid used.17The onsets and peak intensities of withdrawal symptoms for different opioid analgesics are presented in table 3.Opioid tolerance is a predictable pharmacologic adaptation. Continued opioid exposure results in a rightward shift in the dose–response curve, and patients require increasing amounts of drug to maintain the same pharmacologic effects. The phenomenon of tolerance develops to analgesic, euphoric, sedative, respiratory depressant, and nauseating effects of opioids but not to their effects on miosis and bowel motility (constipation).16,17The degree or gradation of opioid tolerance is generally related to duration of exposure, daily dose requirement, and receptor association/disassociation kinetics.16–18Opioid agonists binding to the same receptor may show asymmetric cross-tolerance depending on their intrinsic efficacy.14,16For example, patients treated with sufentanil, an agonist having high intrinsic efficacy and requiring low receptor occupancy for a given analgesic effect, develop tolerance more slowly than to opioids having low intrinsic efficacy, such as morphine.18,19Although there are no clear gradation guidelines, individuals requiring the equivalent of 1 mg or more intravenous or 3 mg or more oral morphine per hour for a period greater than 1 month may be considered to have high-grade opioid tolerance.20,21Tolerance is observed in patients to whom opioids are legitimately prescribed for pain management as well as in those abusing this class of drug. In general, the higher the daily dose requirement, the greater is the degree of tolerance development.16,19,20This is of importance for many patients and caregivers who perceive an increasing opioid dose requirement as reflecting harmful addiction rather than a normal adaptation to this class of analgesics.4,20,21Several types of opioid tolerance, including innate and acquired, have been characterized.14–16Innate tolerance refers to preexisting insensitivity, which is genetically determined and hence is present before drug exposure. True tolerance is acquired after multiple exposures.16,21This can be of three types: pharmacokinetic tolerance, learned tolerance, and pharmacodynamic tolerance. Pharmacokinetic tolerance refers to changes in distribution or metabolism of the drug, usually by enzyme induction and subsequent acceleration in metabolism. Opioids are biotransformed in the liver by two types of metabolic processes. Phase I reactions include oxidative and reductive reactions, such as those catalyzed by the cytochrome enzyme system (P-450), and hydrolytic reactions.22,23Phase II reactions involve conjugation of a drug or its metabolite to an endogenous substrate, such as d-glucuronic acid, generating highly hydrophilic molecules that are excreted primarily by the kidneys. With the exceptions of the N -dealkylated metabolite of meperidine and the 6- and possibly 3-glucuronides of morphine, opioid metabolites are generally inactive.16,17,22,23Because P-450 is inducible by a host of compounds including opioids, barbiturates, and antiepileptics, patients exposed to these drugs for long terms can metabolize some opioids faster, thus producing pharmacokinetic tolerance.16,22There is good evidence that drug metabolism by genetically variable P-450 can also influence the development of tolerance and dependence.22A second type of tolerance, termed learned tolerance , refers to a reduction in the effects of a drug due to compensatory mechanisms that are learned. For example, an opioid abuser learns to behave normally (e.g. , walking in a straight line) in spite of intoxication. Learned tolerance is also observed in methadone maintenance programs where abusers mask the effects of methadone so that a higher dose will be prescribed.21,23Perhaps the most important form of tolerance relevant to opioids is pharmacodynamic tolerance. Pharmacodynamic tolerance has been related to neuroadaptive changes that take place after long-term exposure to the drug. These include changes in receptor density and alterations in receptor coupling to G proteins and signal transduction pathways.16,21,24Basic research has provided a better understanding of the cellular and molecular mechanisms mediating pharmacodynamic opioid tolerance.16,21,25These mechanisms occur at two distinct levels. The first occurs at the level of the opioid receptor and involves receptor desensitization on long-term or repeated exposure to opioids.25The concept of receptor desensitization underlies the classic hypothesis of opioid tolerance.16,25Opioid receptors on the cell surface become gradually desensitized by various mechanisms such as reduced transcription and subsequent decreases in the absolute number of opioid receptors (down-regulation), reduction in the number of opioid receptors on the cell surface by active endocytosis and receptor trafficking from cell surface to the interior of the cells (internalization), and the uncoupling of opioid receptors from underlying G proteins.16,21,25,26However, this classic hypothesis that tolerance is primarily related to receptor desensitization has yet to be proven.A second mechanism proposed to explain pharmacodynamic tolerance involves up-regulation of the cyclic adenosine monophosphate (cAMP).27Acutely, opiates inhibit the functional activity of the cAMP pathway by blocking adenyl cyclase, the enzyme that catalyzes the synthesis of cAMP. However, with long-term opiate exposure, the cAMP pathway gradually recovers, and tolerance develops. Increased synthesis of cAMP may be responsible for physical dependence and physiologic changes associated with withdrawal. In this regard, the activity of the cAMP pathway increases far above baseline levels after abrupt discontinuance of opioid binding.27,28Up-regulation of cAMP has been most clearly demonstrated in the locus ceruleus of the brain,27but up-regulation within the dorsal horn of the spinal cord seems to be responsible for tolerance to opioid-induced analgesia.28Other areas where such cAMP up-regulation has been demonstrated include the nucleus accumbens, ventral tegmental area, periaqueductal gray, amygdala, dorsal horn of the spinal cord, and myenteric plexus of the gut.28Long term-tolerance may represent a persistent neural adaptation.26–29This phenomenon may be observed in patients who discontinued prescribed or illicit opioid use many months or years previously but continue to exhibit opioid insensitivity. Long-term adaptations at the molecular and cellular level include (1) induction of transcription factors, such as δ Fos B, which regulate the function of several genes in a stable fashion, thus initiating neuronal plasticity; (2) activation of the central glutaminergic system; and (3) increased synthesis of spinal dynorphin.26–29Mao, Mayer, and coworkers29–32have provided strong evidence to suggest that glutamate and N -methyl-d-aspartate (NMDA) receptors play a critical role in the development of opioid tolerance and increased pain sensitivity. The role of NMDA receptor activation in the superficial laminae of the dorsal horn is particularly important.30Prolonged exposure to morphine indirectly activates NMDA receptors via second-messenger mechanisms and also down-regulates spinal glutamate transporters.31The resultant high synaptic concentration of glutamate and NMDA activation contributes to opioid tolerance and abnormal pain sensitivity, by various mechanisms. These include an influx of calcium, activation of protein kinase C, production of nitric oxide, and finally, neuronal apoptosis.29,32Spinal dynorphin also seems to play an important role in the development of opioid tolerance and hyperalgesia.33Concentrations of this endogenous opioid peptide increase after continuous exposure to μ-opioid receptor agonists.33Treatment with dynorphin antiserum27,33and NMDA receptor antagonists such as ketamine may attenuate the development of long-term tolerance to the analgesic effects of opiates.30Anesthesiologists are likely to deal with a variety of opioid-dependent patients. The majority are those with chronic pain conditions who have been taking opioid analgesics for a prolonged period (months to years).3–7Clinical surveys of long-term opioid use in patients with both cancer and non–malignancy-associated pain have not shown escalating drug dosage to be inevitable; however, some degree of dose increase over time is often observed. This increase in dose requirement may be indicative of tolerance development, progression of disease, or both factors.34Nugent et al. 35evaluated transdermal fentanyl (Duragesic; Janssen Pharmaceutical Products, Titusville, NJ) dose escalation in 73 patients with pain related to terminal malignancy. They noted that the initial fentanyl dose of 75 μg/h increased approximately 25% to a final median dose of 100 μg/h. Thirty-two of 73 patients initially enrolled continued the drug until or nearly until death (median, 2.9 months; range, 1–23 months). One criticism of this study is that the relatively short lifespan of patients enrolled did not allow sufficient time for the full extent of tolerance and dose escalation to be observed. A careful review of the data indicates that the Duragesic dose range was very wide (25–700 μg/h) and that patients with longer survival required the highest doses and exhibited the greatest degree of dose escalation.35Eight of 16 patients who received fentanyl for 3 months or longer required dose escalation, and 3 patients required dose increases to 300 μg/h or greater.A second group exhibiting tolerance includes opioid abusers (opioid addicts). These patients are generally more problematic in terms of assessment and management.3–6The exact prevalence of opioid addicted patients presenting for surgery is not known but may be expected to vary depending on setting, type of surgery, prevalence in the local and regional population, and the ability of the physician to screen or detect these patients.Heroin is the most commonly abused opioid. Approximately one adult among three who tries heroin becomes addicted to this drug.21Of patients entering treatment for heroin dependence in 1998 in the United States, 50% were non-Hispanic white, 25% were Hispanic, and 22% were non-Hispanic black.‡§‖36Heroin is readily available on the illicit market but has varying levels of purity. Each 100-mg bag of powder in early 1990 had only 4 mg (range, 0–8 mg) of heroin, and the rest was inert or sometimes contained toxic adulterants such as quinine. In the mid-1990s, street heroin reached 45–75% purity. In some large cities, 90% pure heroin was made available. Thus, heroin, which initially required intravenous injection, could be smoked or administered intranasally (snorted). Only 37% of new heroin abusers now inject the drug.§table 4).A unique subset of opioid-tolerant patients, who are neither abusers nor those to whom opioids are prescribed for chronic pain, are former addicts enrolled in long-term methadone maintenance programs. Many of these individuals have not been users for many years, are gainfully employed, and enjoy normal lifestyles. Nevertheless, they are exposed to relatively large doses of methadone, 25–100 mg/day, and, as might be expected, exhibit high-grade tolerance to the antinociceptive effects of opioids.15,38There are no published research data on how to best address the concerns of this particular subclass. The anesthesiologist and pain specialist may devote time to allay patient apprehensions that they may lose control and possibly relapse or that their pain will be inadequately controlled. Patients may be reassured that despite a previous history of opioid dependency, effective pain control is an achievable goal and that the risk of relapse can be minimized.3,15,37,39,40The patient, addictionologist, and rehabilitation counselor may meet before surgery and develop a management plan. Together, they may formulate and agree to follow a realistic protocol that would minimize but not eliminate pain perception, while avoiding excessive opioid doses that might lead to recurrence of addictive disorder15,40,41(table 5). A practical approach might include the use of a medication agreement or contract, setting appropriate goals for pain intensity scores as well as daily dose of analgesic, and a method of analgesic administration. Patient monitoring may include drug screens, pill counts, and careful documentation of the postoperative course.13,39,40A final subset of opioid-dependent patients is those who have well documented chronic pain and who, superficially, resemble opioid abusers by virtue of their often obsessive drug-seeking behavior. These patients are usually found to have visited numerous physicians and have filled multiple prescriptions for opioids. In actuality, these individuals are not addicted but undermedicated and are only seeking adequate pain relief. This phenomenon was not recognized until recently, and has been termed pseudoaddiction by Weissman and Haddox.42Its prevalence is unknown, but it may result in the treatment team becoming negatively biased against the patient and denying him or her adequate opioid coverage. Pseudoaddictive behavior generally reflects patients’ attempts to compensate for development of tolerance, progression of metastatic disease, or worsening of pain in settings where patients have become more functional. In general, pseudoaddictive patients can be differentiated from true drug abusers because increasing doses of opioids and improvement in pain control usually eliminate the drug-seeking behavior.42Finally, it is relevant to note that methadone-maintained and other opioid-tolerant patients are relatively pain intolerant and demonstrate significantly increased sensitivity during cold pressor and thermal testing.38,43It has been hypothesized that continuous opioid receptor occupation produces hyperalgesia during less painful states; thus, these patients are unable to cope with sudden acute pain.43–45Therefore, after surgery or other settings of acute pain, caregivers should not restrict medicating opioid-dependent patients, but rather treat the pain aggressively, while being aware of the altered pharmacokinetic–pharmacodynamic and behavioral issues involved.38,40,46This necessitates a good assessment strategy and formulation of a perioperative management plan to provide adequate comfort to this particularly pain-sensitive population.There are several general principles that help to guide the anesthesiologist and pain specialist with perioperative pain management. First and foremost is to uncover the fact that the patient is an opioid user or an abuser and to recognize that issues related to physical and psychological dependence and opioid tolerance could profoundly influence the postoperative course. The importance of patient assessment and early recognition cannot be overemphasized, because failing this essential first step, principles that follow become less relevant.5–7,41The assessment strategy aims at correct identification of the opioid-abusing patient from dependent individuals with chronic pain conditions.15,47–49The true abuser should be detected, whereas legitimate users are not to be falsely labeled as addicts. In other words, both “false-positive” as well as “false-negative” rates should be low.49–51However, this is easier said than done because of drug-seeking behavior associated with pseudoaddiction.42,52Alternatively, patients who achieve effective pain control may take extraordinary steps to maintain an adequate supply of medication. Although indicative of addictive drug seeking, such behavior may in actuality reflect the efforts of an extremely anxious patient to maintain tolerable pain relief and prevent undermedication.47–49,52Table 4outlines the underlying principles that help clinicians to differentiate patients with chronic pain and opioid abusers.Patients with substance use disorders to alcohol, marijuana, or nicotine show a higher incidence of dependence on other substances than the general population. This phenomenon has been termed cross-addiction or polydrug abuse .21,48,50,51Nearly 70% of opioid addicts in the United States are dependent on either cocaine or other habituating substances.48,50Opioid-dependent patients with superimposed cocaine dependence may present additional problems for acute caregivers, including hemodynamic instability and extreme emotional lability.21,53Some opioid-dependent patients are also codependent on benzodiazepines and other anxiolytics.21By simply focusing on opioid dependency issues and not accounting for or administering adequate doses of benzodiazepines, these individuals may experience severe withdrawal reactions, including anxiety, agitation, and confusion.46,47,52,53Applying Diagnostic and Statistical Manual of Mental Disorders , 4th edition,13criteria for drug abuse to patients taking prescribed opiates for a chronic pain problem is difficult.46,53,54Therefore, special assessment criteria must be developed and applied.54–56A retrospective case review identified some patient characteristics, such as recent polysubstance abuse, early prescription abuse, especially oxycodone, and aberrant drug-seeking behavior, as predictive of later opioid abuse.55Two recently published studies addressed this assessment issue.57,58Chabal et al. 57introduced a five-point prescription opiate abuse checklist that is easy to use, although it may lack sensitivity (table 6). Compton et al. 58developed a more detailed 42-item screening tool called the Prescription Drug Use Questionnaire that may help clinicians to uncover opioid abuse in chronic pain patients. These assessment tools are still in preliminary stages of development, and large-scale multicenter trials are warranted before their widespread application. A major problem with abuse checklists and questionnaires is that some of the criteria used for assessment necessitate prolonged physician contact with the patient and hence may be difficult to apply in acute perioperative settings.54,57,58During patient assessment, the anesthesiologist should recognize that the terms opioid user or abuser may be considered highly sensitive labels.53,55,56Patients are keenly aware of the significant social stigma surrounding opioid dependency and are entitled to privacy and the right to confidentiality. The anesthesiologist should develop a clear management strategy that maintains a balance: to gain patient trust with an understanding and caring approach while being prepared to overcome high-grade tolerance with liberal doses of opioid and nonopioid analgesics.3–5,7,41The anesthesiologist should also be aware of the rapidly changing profile of opioid-based analgesia. Newly developed and marketed opioids often do not have names that are readily recognizable as opioids but represent potent or long-acting preparations that can confer a high degree of tolerance and dependence. Examples include (1) rapid-acting or novel-delivery preparations, Actiq (Cephalon Inc., West Chester, PA; fentanyl oralet), Nasal Stadol (Bristol-Myers Squibb, New York, NY; butorphanol), and Oxy-IR (immediate-release oxycodone) (Purdue-Pharma, Stamford, CT); (2) sustained-release preparations containing fentanyl, Duragesic (fentanyl transdermal patch) or morphine (Kadian; [Elan Corporation, Dublin, Ireland], Avinza [Mayne Pharma (USA), Paramus, NJ], MS-Contin [Purdue-Pharma]); and (3) less often prescribed preparations containing codeine (Fioricet with codeine, Fiorinal with codeine [Sandoz Pharmaceuticals, East Hanover, NJ]), hydrocodone (Hycodan [Endo Laboratories, Chaddsford, PA]), and methadone (Dolophine).It should also be recognized that some patients presenting to the anesthesiologist or preadmission testing unit physicians may not realize that they are opioid dependent and may unintentionally deny the possibility. Patients may not know that opioids have been prescribed to them or may not recognize that escalations in their daily need for pain relievers reflects tolerance development.15,21Although most patients are aware that morphine and Demerol (Sanofi-Synthelabs, New York, NY) are narcotics, many are not aware that they may have been given opioids of even greater potency for treatment of arthritis and low-back pain.Other patients may consciously deny or underplay reporting opioid use or the amount of drug consumed.21,37,41,46The latter scenario is likely to occur in patients highly addicted to opioids. In fact, these are the patients who must be identified before induction of anesthesia, to minimize postoperative risks of undermedication and inadequate analgesia. It should be understood that tolerance to any one opioid preparation results in clinically measurable insensitivity to most others. It does not matter whether individuals are using legally prescribed oxycodone or abusing street heroin—both exhibit a diminished response to intraoperative doses of fentanyl and postoperative doses of morphine.38,46,56,59In same-day surgical settings, not recognizing that a patient is highly opioid dependent may result in inadequate pain relief and an unscheduled hospital admission for pain management. In many cases, the onus of recognition falls on the anesthesiologist, either in preadmission testing or, in the worst-case scenario, just minutes before the scheduled start of the procedure. An increased clinical index of suspicion is useful especially with patients who exhibit a chronic pain condition, those to whom opioids have been recently prescribed, and others whose lifestyle, general appearance, or general physical examination (e.g. , multiple needle marks, thrombosed superficial veins, and skin abscesses) are suggestive of harboring an addictive disorder.5–7,39Finally, it is worth emphasizing that the immediate perioperative period is not the optimal time to attempt detoxification or rehabilitation management for any patient abusing opioids.7,41,49Although obviously important, such issues should be dealt with later in the postoperative period, when the patient is stable and pain has declined in intensity.There are few controlled studies or scientifically rigorous sources of data available to guide the anesthesiologist in optimizing anesthetic and analgesic care, despite the increasing prevalence of opioid dependency.5–7,41,44Perioperative management of opioid-dependent patients is not discussed in any major anesthesiology textbook. The majority of scientific literature in this area is comprised of case reports that include recommendations for patient treatment, often based on the authors’ experience and expertise. We have summarized pertinent clinical findings from a number of case reports and, together with suggestions provided by pain management specialists at major medical centers and our experience caring for opioid-dependent patients, developed guidelines that may improve postoperative analgesia and patient satisfaction. These guidelines, although not tested scientifically, have been advocated in settings of opioid dependency and receptor down-regulation and serve as a backdrop against which future controlled clinical trials may be planned.Perioperative management of opioid-dependent patients begins with preoperative administration of their daily maintenance or baseline opioid dose before induction of general, spinal, or regional anesthesia. Patients should be instructed to take their usual dose of oral opioid on the morning of surgery. Because most sustained-release opioids provide 12 h or more of analgesic effect, baseline requirements will generally be maintained during preoperative and intraoperative periods. Thereafter, baseline requirements may be provided orally, particularly after ambulatory surgery, or parenterally for those recovering in the hospital from more invasive procedures.5,41,44Recovering addicts enrolled in a
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