__________________________________________________ Responsible Prescribing of Controlled Substances
Harm Reduction Harm reduction measures are primarily employed to minimize the morbidity and mortality from opioid abuse and to reduce public nuisance. As a part of this effort, measures to prevent and minimize the frequency and severity of overdoses have been identified. Enrollment in opioid substitution therapy, with agents such as methadone and buprenorphine, substan- tially reduces the risk of overdose as well as the risk for infection and other sequelae of illicit opioid use [1; 2; 70]. Detoxification and Withdrawal The process of tapering patients with opioid dependence from agonist therapy is often referred to as detoxification, or more accurately, medically supervised withdrawal. Its purpose is to eliminate physical dependence on opioid medications. It can be considered the medically supported transition to a medication-free state or to antagonist therapy. A careful and thorough review of the risks and benefits of detoxification should be provided and informed consent obtained from patients prior to choosing this option. Detoxification alone should not be considered a treatment and should only be promoted in the context of a well-planned relapse-prevention program [2; 24; 32; 70]. Discontinuation of opioid use must be implemented slowly and cautiously to avoid a marked abstinence syndrome. Withdrawal symptoms may not begin for days after abrupt discontinuation of methadone or buprenorphine given their longer half-lives. Protracted abstinence, or post-acute withdrawal, may last for several months and is characterized by asthenia, depression, and hypotension. Post-acute withdrawal is more likely to occur with methadone than other opioids [2; 32; 70]. The three primary treatment modalities used for detoxifica- tion are opioid agonists, non-opioid medications, and rapid and ultra-rapid opioid detoxification. The most frequently employed method of opioid withdrawal is a slow, supervised detoxification during which an opioid agonist, usually metha- done, is substituted for the abused opioid. Methadone is the most frequently used opioid agonist due to the convenience of its once-a-day dosing. Methadone is highly bound to plasma proteins and accumulates more readily than heroin in all body tissues. Methadone also has a longer half-life, approximately 22 hours, which makes withdrawal more difficult than from heroin. Substitution therapy with methadone has a high initial dropout rate (30% to 90%) and an early relapse rate. Alternative pharmacologic detoxification choices (all off-label) include clonidine (with or without methadone), midazolam, trazodone, or buprenorphine [32; 71; 80; 81; 82].
Many opioid withdrawal symptoms, such as restlessness, rhinorrhea, lacrimation, diaphoresis, myosis, piloerection, and cardiovascular changes, are mediated through increased sympathetic activation, the result of increased neuron activity in the locus coeruleus. Non-opioid agents (such as clonidine), which inhibit hyperactivation of noradrenergic pathways stemming from the locus coeruleus nucleus, have been used to manage acute withdrawal [71; 80]. The first non-opioid treatment approved for the management of opioid withdrawal symptoms was lofexidine, approved in 2019. In studies, lofexi- dine resulted in less severe withdrawal symptoms and greater treatment retention than placebo [83]. However, some withdrawal symptoms, including anxiety and myalgias, are resistant to clonidine; benzodiazepines and non- steroidal anti-inflammatory agents may be necessary to treat these symptoms. To mitigate withdrawal symptoms and assist in detoxification, alpha2-agonists, opioid agonist-antagonists, benzodiazepines, and antidepressants have been used [71; 80]. Following detoxification, patients may feel exhausted and weak. Other complications, such as slight variations in hemodynamic status and gastrointestinal tract symptoms, follow quickly and may take several days to resolve. Muscle cramps and low back pain can be treated with nonsteroidal anti-inflammatory drugs [80]. However, the newer cyclooxygenase-2 (COX-2) inhibitors may be advantageous because they produce fewer gastrointes- tinal side effects [71]. Insomnia is a frequent aspect of acute and protracted withdrawal, as opioids disrupt the normal sleep-wake cycle and many addicts require narcotics to sleep. Although long-term disruption of the normal sleep-wake cycle cannot be corrected rapidly, melatonin (3 mg), benzodiaz- epines, or antihistamines can be used with beneficial effects. Hypnosis and relaxation techniques are nonpharmacologic methods that may also be used. Biopsychosocial treatments offered in addition to pharmacologic detoxification treatments may positively impact treatment retention and completion, results at follow-up, and compliance [2; 71]. Agonist Replacement or Abstinence Therapy Two principle treatment modalities are offered for patients with opioid use disorder: agonist maintenance (also referred to as medication-assisted treatment) or detoxification followed by outpatient or residential drug-free treatment. Both can be effective, with no clear indication for each, although agonist maintenance leads to greater treatment retention. A reason- able approach is initial outpatient or residential treatment referral for patients relatively new to treatment, with agonist maintenance appropriate for patients with history of treatment failures, greater disease severity, or a history of drug overdoses. Naltrexone is best reserved for patients with strong legal incen- tives to abstain, family involvement to monitor treatment, or concurrent enrollment and involvement in a psychosocial intervention [84].
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