Substance Use Disorders and Detoxification

C H A P T E R

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Substance Use Disorders and Detoxification J. Gregory Hobelmann, MD, MPH b Michael R. Clark, MD, MPH, MBA

SUBSTANCE USE AND CHRONIC PAIN The prevalence of substance use disorders in patients with chronic pain is higher than in the general population.1 Over the past 2 decades, opioid analgesic prescriptions have increased to patients with chronic nonmalignant pain, yet prescriptions for nonopioid analgesics did not significantly change.2–3 Approximately two-thirds of patients in clinics specializing in pain management are prescribed opioid analgesics, which is about 8 million people in the United States.4–6 In a study of primary care outpatients with chronic noncancer pain who received at least 6 months of opioid prescriptions during 1 year, behaviors consistent with opioid abuse were recorded in about 25% of patients.7 Review articles have indicated that addiction in patients with chronic noncancer pain ranges from 0% to 50%, with 20% being the most consistent approximation.8–10 This compares to an estimated 8.6% in the general population, according to the National Institute on Drug Abuse.11 Specifically for opioid use disorders, one study showed that the frequency of opioid use disorders was 4 times higher in patients receiving opioid therapy than in the general population (3.8% vs. 61.3%) and even higher in patients who received methadone maintenance therapy for the treatment of opioid dependence (55.3% to 61.3%).12–13 Determining the presence of a substance abuse disorder usually involves the problem of how to evaluate the patient with chronic pain who is prescribed controlled substances with abuse potential.14–15 Individuals with substance use disorders are more often initiated and continued on opioid therapy for noncancer pain than those without substance use disorders and rates of opioid use were 4 times higher for those with substance use disorders than those without substance use disorders. In those with an opioid use disorder specifically, that rate of opioid use was 7 to 8 times higher. In addition, those with substance use disorders were much more likely to receive higher doses, a larger supply, and more potent medications.16 A recent review of the effectiveness and risks of long-term opioid therapy for the treatment of noncancer pain found that no study of opioid versus nonopioid therapy evaluated longterm outcomes related to pain, function, quality of life, opioid use, or addiction. It also confirmed that there is evidence that opioid therapy is associated with increased risk for abuse and overdose and that this risk is dose dependent.17 Comorbid psychiatric disorders also play a role in the complexity of treating patients with chronic pain. Psychiatric disorders are associated with increased physical symptoms, more subjective pain, more aberrant drug behaviors, and are linked to increased opioid use.18–20 For example, pain arising from chronic medical disorders are rated as more severe in the presence of major depression.21 A large prospective trial indicated that common psychiatric disorders, such as depression,

anxiety, and drug use disorders, predict initiation and ongoing regular use of opioids in patients with chronic pain.22 The causes and onset of substance use disorders have been difficult to characterize in relationship to chronic pain. During the first 5 years after the onset of chronic pain, patients are at the highest risk for developing new substance use disorders and additional physical injuries.23 This risk is highest in patients with a history of a substance use disorder, childhood physical or sexual abuse, and psychiatric comorbidity as opioid misuse occurs for a variety of reasons, including self-medication, use for reward, compulsive use because of addiction, and diversion for profit.24–25 Chronic pain is associated with long-term substance use after substance abuse treatment and detoxification. Therefore, addressing and treating patients for their chronic pain could improve their long-term outcome.26 The mechanisms of relapse into substance abuse after treatment in patients with chronic pain are not well understood and probably involve multiple factors; however, a cycle of pain followed by relief after taking medications is a classic example of operant reinforcement of future medication use that eventually becomes abuse. Careful monitoring of patients is essential to prevent this complication in the treatment of chronic pain.27 Research in patients with substance abuse has demonstrated abnormalities in pain perception and tolerance. An increased sensitivity to pain and the reinforcing effects of relieving pain with substance use suggest a different mechanism for the development of substance abuse in patients with chronic pain. Patients with substance use disorders have increased rates of chronic pain and are at the greatest risk for undertreatment with appropriate medications and subsequent self-medication with illicit drugs.28 Almost a quarter of patients admitted to an inpatient residential substance abuse program and over a third of patients in a methadone maintenance program reported severe chronic pain, many of whom also had pain-related interference in functioning.28 It also appears that patients with co-occurring substance abuse and pain are less likely to complete a substance abuse program than those without pain.29 Ethical principles such as beneficence, quality of life, and autonomy can provide particularly useful guidance for the use of chronic opioid therapy, recognizing that benefits should be optimized in a context of risk management.30 

RISKS OF PHARMACOLOGICAL TREATMENT FOR CHRONIC PAIN OPIOIDS Opioids are effective in the treatment of chronic nonmalignant pain in reducing pain, pain-related disability, 419

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depression, insomnia, and physical dysfunction in the short term (months), but evidence is lacking for their long-term (>1 year) effectiveness.17,31 Nonetheless, opioids are widely considered to be appropriate treatment for various chronic pain conditions. For example, opioids are considered second-line medications for the treatment of neuropathic pain conditions and may be considered first-line treatments in certain circumstances (i.e., acute neuropathic pain, during periods of titration of first-line agents, and exacerbations of neuropathic pain).32 In the past, it was felt that a constant, rather than intermittent “as needed,” dosing should be followed to maintain analgesic effect, but more recent recommendations indicate that long-acting opioids at high doses are recommended only in specific circumstances with severe intractable pain that is not amenable to short-acting or moderate doses of long-acting opioids.33 Using an intermittent schedule can reduce tolerance and dependence. If continuous scheduling is used, most experts agree that opioids with slow onset of action and longer duration of action are preferred to minimize the initial euphoria and interdose withdrawal symptoms. Extended-release oral medications and transdermal routes of administration decrease these qualities and are generally preferred for long-term use. Opioid dependence is mediated by the actions and interactions of opioid receptors.34 Mesolimbic dopaminergic projections to the nucleus accumbens have been implicated in the development of psychological dependence. In contrast, physical dependence on opioids is probably due to adrenergic activity in the locus ceruleus. However, the treatment of nonmalignant chronic pain with opioids remains the subject of considerable debate with fears of regulatory pressure, medication abuse, and the development of tolerance and dependence. This has created a reluctance to prescribe opioids and, possibly, their underutilization. Despite this, the prescribing of long-term opioids is an accepted practice and the number of opioid prescriptions for noncancer pain continues to increase. With this has come a rise in nonmedical use of prescription opioids, which many feel has reached “epidemic” proportions in the United States. In some cases, this nonmedical use progresses to heroin use, often intravenous use, which has devastating consequences.35 In addition, chronic pain conditions may facilitate the development of tolerance to opioid analgesia.36 This can lead to escalating doses of opioids, and at some point, the side effects (tolerance, dependence, opioid-induced hyperalgesia, constipation, sedation, delirium, urinary retention, immunosuppression) outweigh the benefits of analgesia.37 A thorough evaluation, careful patient selection, and close monitoring are all essential for the safe and effective prescribing of opioids for noncancer pain. There are several useful guidelines for responsible opioid prescribing that are readily available to help practitioners.33,38–39 Predicting which patients are at risk for developing an addiction to opioids has been studied. Demographic factors have not been consistent. Strong predictors include a personal history of substance use disorder and/or mental health disorders.40–41 Self-reported craving has also been shown to be a possible risk factor.42 

BENZODIAZEPINES Benzodiazepines are commonly prescribed for anxiety and insomnia in patients with chronic pain, but no studies have demonstrated any benefit for these target symptoms.43–44 Almost 50% of patients with chronic pain report anxiety symptoms, and 30% of chronic pain patients have a diagnosed anxiety or disorder, such as panic disorder.45–46 In general, however, benzodiazepines are less effective for these conditions than other pharmacotherapies such as antidepressants, anticonvulsants, and mood stabilizers.47 Only a limited number of chronic pain conditions such as trigeminal neuralgia, tension headache, and temporomandibular disorders were found to improve with benzodiazepines.48 In addition, patients may take benzodiazepines for reasons other than treating these conditions, and data suggest that the majority of benzodiazepine use is recreational rather than therapeutic.49 Benzodiazepines have been used for the detoxification of patients with chronic pain from sedative/hypnotic medications and were superior to barbiturates for minimizing symptoms of withdrawal.50 Higher levels of withdrawal symptoms during detoxification predicted relapse to future use of benzodiazepines.51 Benzodiazepines also cause cognitive impairment as demonstrated by abnormalities on neuropsychological testing and electroencephalogram (EEG).52 In patients with chronic pain, use of benzodiazepines was associated with decreased activity levels, higher rates of health care visits, increased domestic instability, depression, and more disability days.53 Combining benzodiazepines with opioids may cause additional problems. Patients often notice the enhanced feelings of euphoria when benzodiazepines are used in combination with opioids, especially if the drugs are misused or abused.49 This combination can also have severe, and sometimes fatal, consequences. From 2000 to 2010, hospital admission rates related to coabuse of benzodiazepines and opioids increased by a staggering 570%, while those related to all other substances declined by approximately 10%.54 In a study of 278 opioid related deaths in Utah, benzodiazepines played a role in up to 80% of the deaths.55 In methadone-related mortality, almost 75% of deaths were attributable to a combination of drug effects and benzodiazepines were present in 74% of the deceased.56–57 Benzodiazepines have also been associated with exacerbation of pain and interference of opioid analgesia, which is mediated by the serotonergic system.58 Concomitant use was also associated with higher mean doses of opioids, longer periods of being prescribed opioids, greater risk of receiving a psychogenic pain diagnosis, and higher rates of being diagnosed with other substance use disorders.59–60 

DIAGNOSIS OF SUBSTANCE USE DISORDERS The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) of the American Psychiatric Association differs considerably from the fourth edition (DSM-IV). The DSM-IV uses the terms substance abuse and substance dependence, with substance dependence being distinguished from abuse by more than a continuum of severity. It was important to distinguish dependence from abuse, because dependence reliably predicted more severe medical sequelae, poorer treatment outcomes, higher rates

CHAPTER 47  Substance Use Disorders and Detoxification

of relapse, and worse overall prognosis. The DSM-V utilizes the term “substance use disorder” (i.e., opioid use disorder and sedative, hypnotic, or anxiolytic use disorder). To be diagnosed with a substance use disorder, patients must demonstrate a pattern of substance use leading to impairment or distress, as manifested by at least 2 of 11 criteria, such as taking the substance in larger amounts or over a longer period of time than was intended, continued use despite negative consequences, tolerance, and dependence. The DSM-IV further specifies among severity: mild (presence of two to three symptoms), moderate (presence of four to five symptoms), severe (presence of six or more symptoms).61 A comparison of patients diagnosed using both the DSM-IV and DSM-V indicated that the majority of patients with a lifetime DSM-IV opioid dependence were now classified as having mild opioid use disorder using the DSM-V.62 The core criteria for substance use disorder in patients with chronic pain include the loss of control in the use of medication, excessive preoccupation with the medication despite adequate analgesia, and adverse consequences associated with the use of the medication.63 Items from the Prescription Drug Use Questionnaire that best predicted the presence of addiction in a sample of patients with problematic medication use were the following: (1) patients believing they were addicted; (2) increasing analgesic dose/frequency; and (3) a preferred route of administration. The diagnosis of addiction in the patient with chronic pain must demonstrate certain drug-taking behaviors that interfere with the successful fulfillment of life activities. Access to opioids may not be a specific problem, because a physician has been prescribing them. If addiction is present, however, the patient may fear that the opioid access will be limited and therefore try to conceal any problematic use of the medication. The presence of maladaptive behaviors is emphasized to diagnose addiction, because physical dependence and tolerance should be recognized as normal physiological phenomena. Increased function and opioid analgesia without side effects, not the avoidance of high dose opioids, are the goals of treatment.64 The evaluation of a patient suspected of misusing medications should be thorough and include an assessment of the pain syndrome as well as other medical disorders, patterns of medication use, social and family factors, patient and family history of substance abuse, and a psychiatric history.65 Reliance on medications that provide pain relief can result in a number of stereotyped patient behaviors that are often mistaken for addiction. Persistent pain can lead to increased focus on opioid medications. Patients may take extraordinary measures to ensure an adequate supply even in the absence of addiction. This may be manifested as frequent requests for higher medication doses and larger quantities of medication or seeking medication from additional sources. Patients may understandably fear the reemergence of pain and withdrawal symptoms if they run out of medication. Drug-seeking behavior may be the result of an anxious patient trying to maintain a previous level of pain control. In this situation, the patient’s actions define pseudoaddiction that results from the therapeutic dependence and current or potential undertreatment, but no addiction.66–68 These behaviors resolve once adequate opioid therapy is prescribed.

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In patients with higher risk of addiction, prevention begins with a treatment contract to clarify the conditions under which treatment with opioids will be provided. Elements of a contract emphasize a single physician being responsible for the prescription of the medication, and, in advance, describe for the patient all conditions under which continued use of opioids would be inappropriate. Under optimal circumstances, opioid contracts attempt to improve compliance by distributing all information and utilizing a mutually designed, agreed upon treatment plan that includes consequences for aberrant behaviors and incorporated the primary care physician to form a “trilateral” agreement with patient and pain specialist.69–71 When there is concern that a patient will have difficulty taking medications as directed, a policy of prescribing small quantities of medications, performing random pill counts, and not refilling lost supplies should be explicitly discussed and then followed. External sources of information such as urine toxicology testing, interviews with partners or family members, data from prescription monitoring programs, and review of medical records can improve detection of substance use disorders.72–73 Patients who denied using illicit substances that were detected on urine toxicology are more likely to be younger, receiving workers’ compensation benefits, and have a previous diagnosis of polysubstance abuse.72 The occurrence of any aberrant medication-related behaviors should prompt evaluation for addiction. Even when the diagnosis of a substance use disorder is suspected in patients taking opioids for chronic pain, behaviors such as stealing or forging prescriptions is relatively uncommon.74 The more serious aberrant behaviors consistent with addiction also include selling medications, losing prescriptions, using oral medications intravenously, concurrent abuse of alcohol or other illicit drugs, repeated noncompliance with the prescribed use of medications, and deterioration in the patient’s ability to function in family, social, or occupational roles. Concerns by family or friends about the patient’s pattern of medication use, an appearance suggesting intoxication, or the patient having difficulties with functional abilities require in-depth evaluation. Any unwillingness to discuss the possibility of addiction or changes in chronic opioid therapy requires discussion about the patient’s worries and the possible aberrant behaviors, including medication misuse. 

TREATMENT OF SUBSTANCE USE DISORDERS IN PATIENTS WITH CHRONIC PAIN In general, an active substance use disorder is a relative contraindication to chronic opioid therapy. However, it can be accomplished successfully if the clinical benefits are deemed to outweigh the risks. The treatment of this extraordinary subset of patients with chronic pain will always require considerably more effort and frustration on the part of the physician. A strict treatment structure with therapeutic goals, landmarks to document progress, and contingencies for noncompliance should be made explicit and agreed upon by the patient and all the providers of health care. The first step for the patient is acknowledging that a problem with medication exists. The first step for the clinician is to stop the patient’s behavior of misusing

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medications. Then, sustaining factors must be assessed and addressed. These interventions include treating other medical diseases and psychiatric disorders, managing personality vulnerabilities, meeting situational challenges and life stressors, and providing support and understanding. Finally, the habit of taking the medication inappropriately must be extinguished. The patient should be actively participating in an addictions treatment program that will reinforce taking medications as prescribed and examine the possible reasons for any inappropriate use. Relapse is common and patients with addiction require ongoing monitoring even if the prescription of opioids has ceased. Traditional outpatient drug treatment or 12-step programs can provide support for recovery. Relapse prevention should rely on family members or sponsors to assist the patient in getting prompt attention before further deterioration occurs. If relapse is detected, the precipitating incident should be examined, and strategies to avoid another relapse should be implemented. Although the misuse of medications is unacceptable, complete abstinence is not always the most appropriate or optimal treatment of patients with chronic pain. Data suggest that buprenorphine-naloxone may be a safer alternative to provide pain relief for the chronic pain patient with an opioid use disorder.75 Restoration of function should be the primary treatment goal and may improve with adequate, judicious, and appropriate use of medications.76 

LONG-TERM OPIOID THERAPY Long-term opioid therapy remains controversial and may be complicated by many adverse outcomes.77–78 Published guidelines on the use of opioids for chronic nonmalignant pain have been largely based on expert consensus due to lack of strong evidence.79 Outcomes from trials have been inconclusive and there have been no long-term studies comparing opioids to placebo. Nonetheless, long-term treatment with opioids is a widely accepted practice and several up-to-date guidelines exist for the use of opioids in chronic nonmalignant pain. A total approach to the patient including a history of substance abuse, psychosocial comorbidities, and aberrant drug-related behaviors must be considered in an evaluation. Only if these potential risks can be minimized or treated should chronic opioid treatment be considered.33,38–39 Although a risk of addiction exists in all patients, a review and meta-analysis showed that only a small percentage of patients (0.05%) with no previous substance abuse problems developed an addiction when treated with long-term opioids.80 Close monitoring and random drug screening may serve as a deterrent for substance abuse in this population.8 Regardless, each patient requires a careful risk-benefit analysis when starting long-term opioid therapy. 

WHY IS DETOXIFICATION NECESSARY? Detoxification does not necessarily imply that a patient has been given the diagnosis of a substance use disorder. It is simply the process of withdrawing a person from a specific psychoactive substance in a safe and effective manner. Conversely, not all patients diagnosed with a substance use disorder will require detoxification. While addiction may

TABLE 47.1  Indications for Detoxification

Intolerable side effects Inadequate response or benefit Aberrant drug-related behaviors Noncompliance Loss of control of medication use Preoccupation with the medication Continued use despite adverse consequences Refractory comorbid psychiatric illness Lack of functional improvement or impairment in role responsibilities

necessitate detoxification at the onset of drug rehabilitation treatment, there are many reasons that patients must undergo detoxification. Since long-term treatment will have resulted in physiological dependence, discontinuation or substantial dose reduction requires gradual tapering of medication. In the treatment of chronic nonmalignant pain, the ongoing assessment of a therapeutic trial of medication such as opioids may result in the conclusion that the risk-benefit ratio is no longer acceptable (Table 47.1). A carefully planned and monitored detoxification will avoid withdrawal syndrome in a patient who has become physiologically dependent on medications such as opioids or benzodiazepines. 

OPIOID DETOXIFICATION Although physiological opioid dependence can be demonstrated experimentally within days, most patients will not experience withdrawal symptoms unless they have taken opioids regularly for at least several weeks. Withdrawal symptoms vary among individuals, but patients with a history of physiological opioid dependence, opioid withdrawal, or any other drug withdrawal will generally be more likely to experience opioid withdrawal after shorter periods of use.81 Regardless of total daily dose, once physiological dependence is established, abrupt discontinuation of opioids will precipitate acute withdrawal. Even a reduction in dose can precipitate withdrawal to a lesser degree. Patients taking opioid analgesics on a variable schedule are at higher risk for experiencing intermittent withdrawal if they have become physiologically dependent. Even a long overnight dosing hiatus from a short half-life opioid can cause significant withdrawal symptoms. However, patients on a variable schedule may be at less risk for developing dependence if low and infrequent dosing is maintained. Exacerbations of pain or intermittent withdrawal symptoms relieved by taking medications are highly reinforcing and a common factor in failure of detoxification. Patients with these experiences will require longer tapering schedules and more support to overcome this conditioned habit. The essential element for successful opioid detoxification is gradual tapering of the dose of medication. Opioid withdrawal is generally not dangerous except in patients at risk from increased sympathetic tone (e.g., increased intracranial pressure or unstable angina).81 However, opioid withdrawal is very uncomfortable and distressing to patients with symptoms including cravings, nausea, emesis, diarrhea, agitation, anxiety, muscle tension and aches, bone pain, insomnia, increased lacrimation, yawning, and shaking. Patients with pain are often particularly miserable during opioid withdrawal because of the phenomenon of rebound pain. Increases in pain can occur

CHAPTER 47  Substance Use Disorders and Detoxification

even if the analgesic effects of opioid therapy had not been appreciable. Although it is generally not possible to avoid discomfort completely, the goal of detoxification is to ameliorate withdrawal as much as is clinically practical. Explaining the treatment plan to patients before detoxification begins is critical. In particular, patients should know to expect worsening of pain and should have concrete short-term goals on which to focus, such as improvement in withdrawal symptoms, increasing functional abilities, or an alternative analgesic trial when withdrawal has resolved. The projected length of taper is typically a balance between the expected severity of withdrawal symptoms (increased with faster tapers) and their expected duration (shorter with faster tapers).

SETTING Although detoxification can be accomplished in either inpatient or outpatient settings, the inpatient setting offers more intensive monitoring, supervision, and other support that generally allows for a faster taper schedule. Indications for inpatient detoxification include the failure of outpatient detoxification attempts, medically unstable patients, comorbid psychiatric illness, unreliable or noncompliant patients, and complicated pharmacological regimens requiring taper of more than one medication or illicit drug.82 However, usually opioid detoxification can be accomplished in the outpatient setting. Outpatient detoxification should be planned not only for discomfort, but also for temporary emotional lability and reduction in function. Compensatory planning might include warning family and work supervisors, planning for a decrease in workload on the job, and even taking vacation or sick leave days. Extensive support with frequent monitoring substantially increases the likelihood of a successful taper. Higher success rates have been reported for patients with better therapeutic relationships or formal treatment programs that have included a period of stabilization on long half-life opioids and then proceed with a taper slowly over a period of months. Office visits should occur at least weekly, but daily contact with the patient proves a major advantage of ensuring success. Most contact with the patient does not have to involve the physician and often can be accomplished with a phone call. A nursing visit to check vital signs and assess the severity of withdrawal can provide enormous help to the patient. This should include allowing the patient to express discomfort and frustration but then focus on the treatment plan and patient’s progress.83 Formal checklists of signs and symptoms such as the Subjective Opioid Withdrawal Scale (SOWS) and the Objective Opioid Withdrawal Scale (OOWS) allow for the objective rating of withdrawal and documentation of the patient’s condition over time (Table 47.2).84 Adjustment to the treatment plan is then based on several sources of information and not just the patient’s complaints. 

AGENTS The primary principle for detoxification is that medication should not be prescribed by a “cookbook” approach but through ongoing patient evaluation and subsequent dosage titration. The simplest strategy institutes a taper of agents that the patient is currently using. This may be a short halflife agent, but offers the advantages of using an agent already

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TABLE 47.2  Opioid Withdrawal Rating Scales

The Objective Opiate Withdrawal Scale Score one point for each sign that is present during a 10-min observation period __ Yawning (≥1 yawn per observation period) __ Rhinorrhea (≥3 sniffs per observation period) __ Piloerection (gooseflesh: observe patient’s arm) __ Perspiration __ Lacrimation __ Mydriasis __ Tremors (hands) __ Hot and cold flashes (shivering or huddling for warmth) __ Restlessness (frequent shifts of position) __ Vomiting __ Muscle twitches __ Abdominal cramps (holding stomach) __ Anxiety (from mild fidgeting to severe trembling or panic) Total score __ (maximum severity = 13) The Subjective Opiate Withdrawal Scale Patients should rate each symptom statement on a scale of 0–4: 0 = not at all, 1 = a little, 2 = moderately, 3 = quite a bit, 4 = extremely __ I feel anxious __ I feel like yawning __ I am perspiring __ My eyes are tearing __ My nose is running __ I have goose flesh __ I am shaking __ I have hot flashes __ I have cold flashes __ My bones and muscles ache __ I feel restless __ I feel nauseous __ I feel like vomiting __ My muscles twitch __ I have cramps in my stomach __ I feel like taking [name of opioid] now Total score __ (maximum severity = 64)

familiar to the patient, simplifies an anxiety-filled process, and avoids the imperfect calculation of dosage equivalence and incomplete cross-tolerance. Short half-life agents possess the disadvantage of pharmacokinetics that may not allow a smooth taper. Serum levels will fluctuate more with increasing dosing intervals. Patients will usually experience mild withdrawal within 4 to 8 hours of dosage reduction. The severity of withdrawal will usually peak with a short half-life agent at 8 to 36 hours; however, it can occur as late as 72 hours. When using these agents, certain procedures can minimize the risks of severe withdrawal symptoms (Table 47.3). The preferable pharmacological strategy is to choose a long half-life pure agonist such as methadone, sustainedrelease morphine or oxycodone, and transdermal fentanyl patches (Table 47.4). Methadone is the only medication approved by the US Food and Drug Administration for detoxification in opioid use disorders.81 This strategy has the primary advantage of more consistent opioid serum

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TABLE 47.3  Short-Half-Life Opioid Taper

TABLE 47.5  Buprenorphine Taper

Determine the total daily dosage being used by the patient Adopt a fixed interval schedule with equal doses every 4–6 h for 48 h Increase the prescribed dose until the patient has no opioid withdrawal symptoms for 48 h Taper the amount of each dose without lengthening the interval between doses Taper the total daily dose approximately 10% every 3–7 days Slowing the taper may be accomplished by the following: 1. Increasing the number of days at a given total dose 2. Decreasing a single dose amount while keeping the remaining doses the same 3. Increasing the time between doses only if the smallest individual dose has been reached

Test for the precipitation of acute withdrawal symptoms by giving an initial dose of 0.1 mg SQ/IM or 1.0 mg SL Determine the total daily dose of the prescribed agent being taken by the patient Estimate the equivalent total daily dose of buprenorphine (0.2 mg SQ/IM = morphine 10 mg PO) Adopt a fixed interval schedule with equal doses every 8–12 h Titrate the dosage until the patient has no withdrawal symptoms for 24–72 h Taper the dose and interval to 0.1 mg SQ/IM or 1.0 mg PO qd Discontinue the medication when the patient experiences no or tolerable withdrawal symptoms

TABLE 47.4  Long-Half-Life Opioid Taper

Determine the total daily dose of the prescribed agent being taken by the patient Estimate by conversion the equivalent total daily dose of the longhalf-life opioid Adopt a fixed interval schedule with equal doses every 6–8 h for 48 h Increase the prescribed dose of long-half-life opioid until the patient has no withdrawal symptoms for 3–5 days Taper the amount of each dose unless the patient can tolerate an interval schedule of dosing every 8–12 h Taper the total daily dose approximately 10% every 3–7 days Increase the number of days at a given total daily dose to slow the taper

levels with less chance of intermittent withdrawal between doses. With a long half-life agent, the onset of withdrawal symptoms should be expected at 12 to 24 hours, although 24 to 48 hours is the usual reported time course. The severity will usually peak at 36 to 96 hours, but can occur up to 1 week later. Substitution, which is not exact, may require some initial titration to achieve dosing equivalence. An initial test dose of the agent can be given to determine the total dose needed. Switching from short to long half-life opioids in anticipation of detoxification may serendipitously prove an effective analgesic strategy. Side effects, intermittent withdrawal, and rebound pain may serve as a general guideline to estimate equivalent opioid doses. Clinical judgment should be used and individual patient characteristics should be considered when applying any table, since there is variance between equivalence charts.85 Another detoxification strategy utilizes the partial agonist/antagonist opioids. The agent most commonly used in this category is buprenorphine or the buprenorphine-naloxone combination (Suboxone) (Table 47.5). The buprenorphine-naloxone combination comes in a 4:1 ratio, respectively, and naloxone is added to prevent intravenous use as it only becomes bioavailable when dissolved and injected.86–87 The use of partial agonist/ antagonists is designed to reduce the severity of withdrawal and cause less reinforcing drug effects. As a result, the taper should be easier and more successful. There is also less risk of respiratory depression, which is an infrequent consequence of overestimating the dosing equivalence with pure agonist substitution. When using partial agonist/antagonists such as buprenorphine, it is important to give a small test dose under the supervision of a provider because of the rare precipitation of withdrawal

IM, Intramuscular; PO, oral (per os); qd, daily (quaque die); SL, sublingual; SQ, subcutaneous.

TABLE 47.6  Adjunctive Agents for Symptoms of Opioid

Withdrawal Symptom

Agent Type

Agent

Diarrhea Rhinorrhea

Bismuth products Antihistamines

Muscle aches Abdominal cramps Insomnia

Muscle relaxants Anticholinergics Antihistamines Antidepressants

Pepto-Bismol Diphenhydramine, loratadine methocarbamol Dicyclomine HCl Diphenhydramine Trazodone, doxepin

symptoms secondary to the partial antagonist effects. The patient should not take the agonist/antagonist until withdrawal symptoms have begun because taking it too soon after the last dose of a pure agonist will likely precipitate withdrawal. If the patient tolerates the test dose, then the titration of dose equivalence substitution can proceed. Buprenorphine-naloxone is effective for outpatient or inpatient detoxification, and improved outcomes when compared to clonidine for detoxification.88–89 Evidence indicates that buprenorphine and methadone are similar with regards to treatment retention and decreasing use of other opioids in patients with nonmalignant pain and an opioid use disorder.90 Buprenorphine-naloxone has been shown to be safe and well tolerated.88–90 

ADJUNCTIVE AGENTS Several nonopioid pharmacological agents are commonly used as adjunctive agents to provide patients additional relief from withdrawal symptoms (Table 47.6). Clonidine, an alpha-2-adrenergic agonist that decreases adrenergic activity, is the most commonly prescribed. Clonidine can help relieve many of the autonomic symptoms of opioid withdrawal, such as nausea, cramps, sweating, tachycardia, and hypertension, which result from the loss of opioid suppression of the locus ceruleus during the withdrawal syndrome.91–92 Other adjunctive agents include nonsteroidal antiinflammatory drugs for muscle aches, bismuth subsalicylate (Pepto-Bismol) for diarrhea, dicyclomine (Bentyl) for abdominal cramps, and antihistamines for insomnia and restlessness. Gabapentin (Neurontin) has also been shown to decrease the severity of coldness, diarrhea, dysphoria, yawning, and muscle tension during opioid withdrawal.93 

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SCHEDULE Unless patients are involved with dangerous aberrant drugtaking behaviors, there is generally no urgency to shorten the duration of opioid detoxification. There is only scant literature examining the pace of tapering in opioid-dependent patients, so clinical judgment must be used.81 The longer the patient has been taking opioids, the more difficulty they are likely to have with withdrawal. The taper will then require more time to be completed. Other factors that tend to increase the difficulty and length of a taper are medical comorbidity and complexity, older age, female gender, and detoxification from multiple agents simultaneously. Detoxification occurs if more difficult in the last stages of the taper, and it should be anticipated that decreases in the dose of opioids would need to be more gradual during this time. If a taper becomes more complicated, the schedule should be extended by decreasing the dosage reductions or lengthening the intervals between reductions. As long as patients are demonstrating ongoing progress, there is generally no reason not to extend an opioid taper over several weeks or even months. Progress can be demonstrated by simple compliance with taper instructions, not using illicit substances, improvement in side effects of opioids, and maintenance of function. 

FOLLOW-UP The process of detoxification does not end with the completion of the opioid taper. Patients can have lingering subacute withdrawal symptoms for weeks. In some circumstances, they can last for months. Insomnia and rebound pain are the most common symptoms, but any of the withdrawal symptoms can reemerge. After the taper, patients who had difficulty with aberrant drug-taking behaviors continue to need increased levels of monitoring and supervision in their treatments because the risk of relapse is high. Patients without a history of addiction and aberrant drug-taking behaviors do not require specialized substance abuse treatment. These patients should be reassured that they do not have an addiction or the diagnosis of substance abuse/dependence. However, any detoxification precipitated by the diagnosis of addiction or medication misuse should have further evaluation and treatment. Referral to an addiction specialist is usually a helpful first step. Furthermore, active ongoing participation in the treatment prescribed for addiction should be a condition of continued pain treatment. For these patients, the prevention of relapse requires a long-term outpatient program of substance abuse rehabilitation. 

BENZODIAZEPINE DETOXIFICATION The technique of a benzodiazepine taper follows the same general principles of an opioid taper.94–95 If patients have been using benzodiazepines only intermittently, there is generally no need for a taper. However, anyone who has been using benzodiazepines continuously for more than two weeks should be tapered to avoid the unpleasant experience of mild withdrawal and the risk of unexpected major withdrawal symptoms. A higher total daily dose and longer duration of use produces a higher risk of significant and potentially life-threatening withdrawal with abrupt cessation. The general features of benzodiazepine withdrawal are similar to those of opioid withdrawal with hyperarousal

TABLE 47.7  Signs and Symptoms of Sedative-Hypnotic

Withdrawal Hyperarousal Agitation Anxiety Hyperactivity Insomnia Fever Neurological Ataxia Fasciculation/myoclonic jerks Formication Headache Myalgia Paresthesias/Dysesthesias Pruritus Tinnitus Tremor Seizures Delirium Genitourinary Incontinence Loss of libido Urinary urgency, frequency Psychiatric Depersonalization Depression Hyperventilation Malaise Paranoid delusions Visual hallucinations Gastrointestinal Abdominal pain Constipation Diarrhea Nausea Vomiting Anorexia Cardiovascular Chest pain Flushing Palpitations Hypertension Orthostatic hypotension Tachycardia Diaphoresis

and hypersympathetic states. However, in its more specific features, the withdrawal syndrome is more similar to the syndrome observed with alcohol (Table 47.7). Similarly, benzodiazepine withdrawal is much more dangerous than opioid withdrawal and includes the potential for seizures, hallucinations, hyperthermia, and delirium tremens. Similar to alcohol withdrawal, when untreated, severe benzodiazepine withdrawal has a higher rate of morbidity and mortality. The two main techniques for detoxification include a taper of the agent a patient has been taking and the substitution of an equivalent dose of a long half-life agent such as diazepam or clonazepam. Another strategy for benzodiazepine detoxification utilizes phenobarbital solution, especially in cases of complex detoxification from

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SECTION VI  Pharmacology and Pharmacologic Modalities

multiple agents such as opioids, sedative-hypnotics, and alcohol. The phenobarbital dose should be determined by a series of test doses and subsequent observation to determine the level of tolerance. In addition, infrequently, the “second generation” benzodiazepines (clonazepam, alprazolam, oxazepam, triazolam) are not fully cross-tolerant with each other or with the more traditional agents. A patient may require higher doses than expected to avoid significant withdrawal symptoms when taking these medications. Benzodiazepine tapers will generally require more time than opioid tapers with less frequent dose reductions. A taper of 6 weeks or more, especially with long half-life agents, is not unusual, and some have recommended a 6-month taper.96 Carbamazepine has been shown to have modest benefit in reducing symptoms of benzodiazepine withdrawal, and, more recently, gabapentin has been utilized by some practitioners, but it has not been studied.95 

with the reinforcement that all treatments should result in benefits that outweigh their risks, the therapeutic relationship will be strengthened and the chances for successful treatment are optimized. 

KEY POINTS l

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CONCLUSION Patients with chronic pain are at increased risk of substance use disorders. However, it is crucial to appreciate that there are many causes for aberrant medication-related behaviors. Misuse of medication is a clinical problem that can be the result of dependence, but it is often the result of inadequate analgesia. This can be due to undertreatment with opioids and other analgesics, disease progression, or tolerance to medications. Eventually, instead of consulting with their physician, the patient may simply take more medication. Without proper instructions, they will often take it inappropriately. If the patient does have an addiction, they will be preoccupied with the medication, have lost control of its use, and continue taking it regardless of the negative consequences they are now suffering. This patient requires specialized evaluation and treatment in addition to the management of their chronic pain syndrome. If careful planning and common principles are applied, detoxification will facilitate the transition from ineffective or problematic treatments to other potentially more effective treatments for pain. Treatments may include drug rehabilitation, but it should not be prescribed for every inpatient undergoing detoxification. By avoiding unpleasant or dangerous withdrawal syndromes and providing the patient

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 he prevalence of substance use disorders in patients with T chronic pain is higher than in the general population. Individuals with substance use disorders are more often initiated and continued on opioid therapy for noncancer pain than those without substance use disorders. Comorbid psychiatric disorders are associated with  increased physical symptoms, more subjective pain, more aberrant drug behaviors, and are linked to increased opioid use. Research in patients with substance abuse has demonstrated abnormalities in pain perception and tolerance. Opioids are effective in the treatment of chronic nonmalignant pain in reducing pain, pain-related disability, depression, insomnia, and physical dysfunction in the short term (months), but evidence is lacking for their long-term (>1 year) effectiveness. A thorough evaluation, careful patient selection, and close monitoring are all essential for the safe and effective prescribing of opioids for noncancer pain. Benzodiazepines have little to no role in treating chronic noncancer pain and are associated with significant risk. To be diagnosed with a substance use disorder (DSMV), patients must demonstrate a pattern of substance use leading to impairment or distress, as manifested by at least 2 of 11 criteria, such as taking the substance in larger amounts or over a longer period than was intended, continued use despite negative consequences, tolerance, and dependence, among others. The occurrence of any aberrant medication-related  behaviors should prompt evaluation for addiction. An active substance use disorder is a strong relative contraindication to chronic opioid therapy.

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