Perioperative Management of Acute Pain in the Opioid-dependent Patient

PAIN 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 increased and has been that continuous opioid receptor these patients are to with acute after surgery or other settings of acute pain, caregivers should not opioid-dependent patients, but rather the pain while of the and behavioral issues a good assessment and of a perioperative management to provide adequate to this particularly are several general that to the anesthesiologist and pain specialist with perioperative pain and is to the that the patient is an opioid or an abuser and to that issues related to physical and psychological dependence and opioid tolerance could influence the postoperative The importance of patient assessment and early be because this first that follow become assessment at of the patient from dependent individuals with chronic pain true abuser should be whereas legitimate users are not to be as In other both as well as should be this is than because of drug-seeking behavior associated with patients who effective pain control may take to maintain an adequate of indicative of addictive drug such behavior may in reflect the of an patient to maintain pain relief and the underlying that to patients with chronic pain and opioid with substance use disorders to or show a higher of dependence on other than the general This phenomenon has been termed or abuse of opioid addicts in the United are dependent on or other patients with dependence may present for acute caregivers, including and emotional opioid-dependent patients are also on and other on opioid dependency issues and not for or adequate doses of these individuals may experience withdrawal reactions, including and and of , for drug abuse to patients taking prescribed opiates for a chronic pain problem is special assessment be and review some patient such as recent abuse, early prescription abuse, especially oxycodone, and drug-seeking behavior, as of opioid published this assessment et al. a prescription opiate abuse that is to although it may et al. a more the that may to opioid abuse in chronic pain patients. These assessment are in of development, and are before their A problem with abuse and is that some of the used for assessment prolonged physician with the patient and hence may be to in acute perioperative patient the anesthesiologist should that the terms opioid or abuser may be considered highly are of the social opioid dependency and are to and the to The anesthesiologist should develop a clear management that a to patient with an understanding and approach while to high-grade tolerance with doses of opioid and anesthesiologist should also be of the of and opioids often not have that are readily as opioids but represent or that can a high degree of tolerance and dependence. include (1) or fentanyl and (2) sustained-release Duragesic transdermal or morphine and (3) often prescribed with with and methadone should also be recognized that some patients presenting to the anesthesiologist or physicians may not that they are opioid dependent and may the Patients may not that opioids have been prescribed to or may not that in their daily for pain reflects tolerance most patients are that morphine and are many are not that they may have been given opioids of greater for treatment of and patients may or opioid use or the of drug is likely to occur in patients highly addicted to opioids. In these are the patients who be before induction of to minimize postoperative of undermedication and inadequate should be that tolerance to one opioid results in to most not individuals are prescribed or abusing street exhibit a response to doses of fentanyl and postoperative doses of not that a patient is highly opioid dependent may result in inadequate pain relief and an for pain In many the of on the in in the before the of the An increased clinical of is especially with patients who exhibit a chronic pain those to whom opioids have been and general or general physical (e.g. , multiple superficial and skin are of an addictive it is that the perioperative period is not the time to or rehabilitation management for patient abusing such issues should be with in the postoperative when the patient is stable and pain has in are or of data available to the anesthesiologist in and analgesic despite the increasing prevalence of opioid management of opioid-dependent patients is not in The majority of in this is of that include for patient often on the experience and have clinical from a number of and, with provided by pain management specialists at medical and experience for opioid-dependent patients, guidelines that may postoperative and patient These guidelines, although not have been in settings of opioid dependency and receptor and as a against which clinical may be management of opioid-dependent patients with preoperative of their daily maintenance or baseline opioid dose before induction of general, or regional Patients should be to take their dose of oral opioid on the of most sustained-release opioids provide or more of analgesic effect, baseline will generally be preoperative and baseline may be provided particularly after surgery, or parenterally for those in the from more addicts enrolled in a