Abstract
The prevalence of substance use disorders in patients with chronic pain is higher than in the general population. The causes and onset of substance use disorders have been difficult to characterize in relationship to chronic pain. Comorbid psychiatric disorders also play a role in the complexity of treating patients with chronic pain. Opioid analgesic prescriptions have increased to patients with chronic nonmalignant pain over the past two decades, despite lacking evidence for their long-term effectiveness. Benzodiazepines are also commonly prescribed for anxiety and insomnia in patients with chronic pain, but no studies have demonstrated any benefit for these target symptoms. Careful monitoring of patients in this setting is essential to prevent substance use disorders from arising or relapsing. If the decision to discontinue opioids or benzodiazepines has been made for any reason, a carefully planned and monitored detoxification will help to avoid withdrawal symptoms in a patient who has become physiologically dependent. Opioid withdrawal is generally not dangerous except in patients at risk for increased sympathetic tone. The essential element for successful opioid detoxification is gradual tapering of the dose of the medication. The technique of benzodiazepine taper follows the same general principles of an opioid taper. However, a higher total daily dose and longer duration of use produce a higher risk of significant and potentially life-threatening symptoms of withdrawal from benzodiazepines. By avoiding unpleasant or dangerous withdrawal syndromes and providing the patient with the reinforcement that all treatments should result in benefits that outweigh risks, the therapeutic relationship will be strengthened and the chances for successful treatment are optimized.
Keywords
benzodiazepines, buprenorphine, chronic nonmalignant pain, detoxification, opioids, substance use disorder
Substance Use and Chronic Pain
The prevalence of substance use disorders in patients with chronic pain is higher than in the general population. 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. 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. 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. Review articles have indicated that addiction in patients with chronic noncancer pain ranges from 0% to 50%, with 20% being the most consistent approximation. This compares to an estimated 8.6% in the general population, according to the National Institute on Drug Abuse. 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%).
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. 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. 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 long-term 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.
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. For example, pain arising from chronic medical disorders are rated as more severe in the presence of major depression. 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.
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. 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. 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. 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. 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. 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. 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. 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.
Risks of Pharmacological Treatment for Chronic Pain
Opioids
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. 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). 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. 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. 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. In addition, chronic pain conditions may facilitate the development of tolerance to opioid analgesia. 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. 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.
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. Self-reported craving has also been shown to be a possible risk factor.
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. 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. In general, however, benzodiazepines are less effective for these conditions than other pharmacotherapies such as antidepressants, anticonvulsants, and mood stabilizers. Only a limited number of chronic pain conditions such as trigeminal neuralgia, tension headache, and temporomandibular disorders were found to improve with benzodiazepines. 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. 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. Higher levels of withdrawal symptoms during detoxification predicted relapse to future use of benzodiazepines.
Benzodiazepines also cause cognitive impairment as demonstrated by abnormalities on neuropsychological testing and electroencephalogram (EEG). 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. 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. 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%. In a study of 278 opioid related deaths in Utah, benzodiazepines played a role in up to 80% of the deaths. 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. Benzodiazepines have also been associated with exacerbation of pain and interference of opioid analgesia, which is mediated by the serotonergic system. 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.
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 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). 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.
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. 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.
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. 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. These behaviors resolve once adequate opioid therapy is prescribed.
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. 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. 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.
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. 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 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. Restoration of function should be the primary treatment goal and may improve with adequate, judicious, and appropriate use of medications.
Long-Term Opioid Therapy
Long-term opioid therapy remains controversial and may be complicated by many adverse outcomes. Published guidelines on the use of opioids for chronic nonmalignant pain have been largely based on expert consensus due to lack of strong evidence. 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. 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. Close monitoring and random drug screening may serve as a deterrent for substance abuse in this population. 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 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.
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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. 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). 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 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. 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. 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 ). Adjustment to the treatment plan is then based on several sources of information and not just the patient’s complaints.
| The Objective Opiate Withdrawal Scale |
| Score one point for each sign that is present during a 10-min observation period |
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| 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 |
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| Total score __ (maximum severity = 64) |
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