Opioid Abuse Treatment & Management

Acute opioid-related disorders that require medical management include opioid intoxication, opioid overdose, and opioid withdrawal. Issues pertaining to treatment of chronic opioid abuse include opioid agonist therapy (OAT), psychotherapy, and treatment of acute pain in patients already on maintenance therapy.

Opioid intoxication

General supportive measures for opioid intoxication are as follows:

• Assess patient to clear airway.
• Provide support ventilation, if needed.
• Assess and support cardiac function.
• Provide IV fluids.
• Frequently monitor the vital signs and cardiopulmonary status until the patient has cleared opioids from the system.
• Give IV naloxone if necessary. Naloxone is a specific opiate antagonist with no agonist or euphoriant properties. When administered intravenously or subcutaneously, it rapidly reverses the respiratory depression and sedation caused by heroin intoxication.

Opioid overdose

Naloxone is effective in treating acute overdose and is first-line treatment.

Because overdoses usually occur in the presence of other people and because medical care is often not sought or is sought too late, at-home naloxone programs have been piloted in several countries. This is a controversial treatment that raises concerns about condoning heroin use, discouraging medical care, and producing side effects that cannot be managed at home. However, the efficacy of these pilot programs should be carefully monitored, as the potential for reducing mortality is high.

Opioid maintenance therapy

Pharmacologic therapy for heroin addiction has focused on ameliorating withdrawal symptoms and reducing cravings. By replacing heroin with legally obtained opioid agonists, many risk factors of the drug-abusing lifestyle can be mitigated.

Methadone maintenance therapy^[10] (MMT) has been the standard of care for more than 30 years. However, the recent advent of buprenorphine maintenance therapy (BMT) is changing the landscape of treatment for opioid-dependent patients.^[11]

Methadone, a long-acting synthetic opioid agonist, can be dosed once daily and replaces the necessity for multiple daily heroin doses. As such, it stabilizes the drug-abusing lifestyle, reducing criminal behaviors, and also reducing needle sharing and promiscuous behaviors leading to transmission of HIV and other diseases.

Methadone is a highly regulated Schedule II medication, only available at specialized methadone maintenance clinics. It is estimated that established methadone clinics can accommodate only 15-20% of US heroin addicts.

Methadone clinics often generate controversy in communities fearful of addicts in various stages of recovery. In addition, some patients are unable to travel to clinics, and others will not enter MMT because of fear of stigmatization. Clearly other options would be beneficial for treatment of chronic opioid abuse.

Buprenorphine is a mu-opioid partial agonist that, like methadone, suppresses withdrawal and cravings. However, the property of partial agonism confers a "ceiling effect," at which higher doses of buprenorphine cause no additional effects. This ceiling effect affords a wider margin of safety than methadone, which can be lethal in overdose. The increased safety of buprenorphine has allowed it to become available by prescription as a Schedule III medication.

Buprenorphine has been combined with naloxone^[12] in a 4:1 ratio (Suboxone) in order to alleviate concerns that the sublingual tablet would be dissolved and injected by addicts. Naloxone is an opioid antagonist that is poorly absorbed sublingually and orally but is well-absorbed intravenously. As a result, an opioid-dependent patient injecting buprenorphine/naloxone will suffer a withdrawal syndrome secondary to naloxone's occupation of mu-opioid receptors.

Office-based treatment of opioid addiction is now possible with BMT.^[13] Physicians wishing to prescribe buprenorphine must meet several criteria, including requirements outlined in the Drug Abuse Treatment Act of 2000. However, physicians who do not meet these criteria can take an 8-hour training course to become certified to prescribe buprenorphine. Currently, physicians are limited to 30 buprenorphine patients, but this restriction may soon be lifted.

Persons with opioid dependence often experience difficulty following current existing pharmacologic treatments designed to reduce or eliminate opioid use. Ling et al studied the efficacy of buprenorphine implants over a 6-month period in patients with opioid dependence. Initial induction with sublingual buprenorphine-naloxone tablets preceded implant placement. Less opioid use was observed (as assessed by urine samples) in patients using the buprenorphine implants compared with placebo implants.^[14]

Historically, l-alpha-acetylmethadol (LAAM) has also been used for opioid-dependence maintenance pharmacotherapy. However, LAAM is associated with prolonged QT interval, and several cases of cardiac arrhythmia and death have been reported. Therefore, LAAM was recently removed from the market in the European Union and was given a black box label by the FDA.

Several Cochrane Database Systematic Reviews about the efficacy of opioid agonist therapy have been published in recent years. While all of these reviews stress the need for larger, multicenter, randomized clinical trials of longer duration, some conclusions can be drawn from existing data.

A review of Cochrane reviews found that high-dose MMT (60-109 mg/d) is more effective in retaining patients in treatment than low-dose MMT (1-59 mg/d). Moreover, methadone at flexible doses was more effective in retaining patients in treatment (RR, 1.23) than buprenorphine. A second systematic review of databases found that low-dose methadone (20 mg/d) was less effective than buprenorphine (2-8 mg/d) and that high-dose methadone (>50-65 mg/d) was more effective than buprenorphine (2-8 mg/d).

Another Cochrane review found that oral substitution treatment was associated with significant reductions in heroin injection and needle sharing, as well as a decrease in patients with multiple sexual partners and a reduction in exchanges of sex for drugs or money.^[15] Importantly, these changes were correlated with reductions in cases of HIV infection.

Although pain is common among opioid-dependent patients, pharmacologic approaches are limited. Tsui et al found that treatment with escitalopram, a selective serotonin reuptake inhibitor, was associated with clinically meaningful reductions in pain severity and pain interference during the initial 3 months of treatment.^[16]

Preventing opioid dependence relapse

A randomized, placebo-controlled trial suggested that an injectable, sustained-release form of naltrexone (Depotrex) increased retention of patients in treatment for opioid abuse.^[17] Further studies are necessary to evaluate the efficacy of this treatment modality.

FDA approval of extended-release IM naltrexone for the prevention of relapse to opioid dependence was based on data from a 6-month, multicenter, randomized, phase 3 study, which met its primary efficacy endpoint and all secondary efficacy endpoints. Once monthly treatment with extended-release IM naltrexone showed statistically significant higher rates of opioid-free urine screens compared with placebo (p< 0.0002).

In a double-blind, placebo-controlled, randomized, 24-week trial, 250 patients with opiate dependence were given monthly injections of an extended-release formulation of 380 mg of naltrexone or placebo.^[18] The study found substantial benefit in the actively treated group, with abstinence rates of 90% compared with 35%. Other measures confirmed this benefit, with a median retention of 168 days in the naltrexone group compared with 96 days in the placebo group, and reduced craving in the naltrexone group. Given the poor therapeutic efficacy of oral naltrexone in most opioid-dependent populations, this intramuscular formulation may be a valuable addition to the methods of treating opioid dependence if its value is verified in subsequent studies over longer therapeutic time periods in diverse groups of patients.

Stress has been associated with impaired decision making and increased risk for relapse, even after long periods of abstinence. In a double-blind, placebo-controlled, randomized protocol, the negative effects of stress on performance were prevented by the beta-adrenoceptor antagonist propranolol as early as after 30 days and as late as 24 months after abstinence began, suggesting a potential role for beta-blockers in decreasing the risk for relapse.^[19]

Because decision-making deficits are common, individuals with more prominent deficits may particularly benefit from treatment in a residential setting.^[20]

Opiate withdrawal

Opiate withdrawal is generally considered less likely to produce severe morbidity or mortality compared with barbiturates and benzodiazepines. Safe withdrawal from opioids is termed detoxification and can be performed as outpatient or inpatient therapy, depending upon the following: presence of comorbid medical and psychiatric problems, availability of social support, and polydrug abuse.

Methadone, buprenorphine, and alpha-2 agonists, such as clonidine and lofexidine, are commonly used pharmacologic methods of detoxification. The use of methadone and buprenorphine is based on the principle of cross-tolerance in which one opioid is replaced with another and then slowly withdrawn. Alpha-2 agonists appear to be most effective in suppressing autonomically mediated signs and symptoms of abstinence^[21] , but they are less effective for subjective symptoms.

Two recent Cochrane reviews compared the efficacy of alpha-2 adrenergic agonists to methadone or buprenorphine for management of withdrawal.^{[22, 23]} Patients experienced decreased side effects and stayed in treatment longer using tapered methadone compared to the alpha-2 agonists clonidine or lofexidine.

Buprenorphine was associated with fewer adverse effects than clonidine, and patients were more likely to complete withdrawal with buprenorphine compared with clonidine. Moreover, a second multicenter randomized trial demonstrated that buprenorphine-naloxone was more effective than clonidine for opioid detoxification. Buprenorphine was equally effective as methadone for withdrawal completion, but withdrawal symptoms appeared to resolve more quickly with buprenorphine.

In summary, data to date suggest that buprenorphine and methadone are more effective than alpha-2 agonists, such as clonidine, for opioid detoxification, with buprenorphine associated with a shorter duration of withdrawal symptoms. However, all of these medications are effective, and the choice may depend in part on availability.

Kunoe et al described use of an investigational naltrexone implant in 56 abstinence-oriented patients who completed inpatient treatment for opioid dependence compared with patients who received usual care instead of the implant. The implant group had an average 45 days less heroin use and 60 days less opioid use than the usual care group over a 6-month period (P < 0.05). The naltrexone implant significantly reduced opioid use compared with usual care.^[24]

Hulse et al compared daily oral naltrexone with a sustained-release naltrexone implant in 70 patients with DSM-IV heroin dependence. Study participants were randomized to receive either daily oral naltrexone (50 mg/d, plus placebo implants) or naltrexone implant (2.3 g, plus placebo tablets). More patients in the oral group had naltrexone serum concentrations less than 2 mg/mL at month 1 (P < 0.001) and month 2 (P < 0.01) compared with the implant group. Return to regular heroin use was observed more in the oral group by 6 months (P =0.003) and at an earlier stage (median 115 d vs 158 d) compared with the implant group. The authors concluded that naltrexone implant is effective in reducing relapse to regular heroin use compared with oral naltrexone.^[25]

Psychotherapies and support groups: Detoxification alone, without ongoing treatment, is not adequate to manage patients.^[26]

Patients in methadone programs often benefit from cognitive behavioral, supportive, or analytical-oriented psychotherapies if they are added to standard drug counseling.

Cognitive behavior psychotherapy primarily focuses on the patient's thoughts and behaviors. Cognitive behavior–based models are widely used in drug rehabilitation programs. Cognitive behavior theories were aimed at substance abuse beginning in the mid 1980s. The techniques used help patients acquire specific skills for resisting substance use and teach coping skills to reduce problems related to drug use. Two major cognitive behavior theories of substance abuse are the following:

• Relapse prevention: Based on the work of Marlatt and Gordon, important relapse prevention concepts and techniques include identification and avoidance of high-risk situations, understanding the chain of decisions leading to drug use, and changing one's lifestyle.
• Cognitive therapy of substance abuse: Developed by Beck and colleagues, cognitive therapy of substance abuse is based on the concept that drug abusers engage in complex behaviors and thought processes, such as positive and negative drug-related beliefs and spontaneous flashes related to drug use before giving in to the actual drug use

Dynamic psychotherapy is based on the concept that all symptoms arise from underlying unconscious psychological conflicts. The major goal of this therapy is to help the patient become aware of these conflicts and develop more adaptive coping mechanisms and healthier methods of resolving intrapsychic conflict.

Group therapy is argued to be especially effective because it can target the social stigma attached to having lost control of a substance. The presence of other group members who acknowledge having similar problems can provide support and be therapeutic in developing alternative methods of maintaining abstinence.

Aversion therapy involves pairing aversive stimuli to cognitive images of opioid use and conversely conjuring images of socially appropriate behaviors such as employment, education, and nondrug behavior.

Narcotics Anonymous (NA): In 1947, NA was formed in Lexington, Ky. NA is based on principles similar to those of Alcoholics Anonymous (AA), including progression through 12 steps of recovery. Some patients have difficulty engaging in the AA-NA approach to recovery; however, these programs do help some people and can provide much needed support for those attempting abstinence.

Although psychosocial therapy is likely to be beneficial in the treatment of opiate withdrawal, the specific type of psychosocial therapy may not be important. A Cochrane review assessed 11 studies involving 1592 patients and explored the effectiveness of any psychosocial intervention combined with any pharmacological intervention versus any pharmacological intervention alone for opioid detoxification treatment. Five different psychosocial interventions (including behavioral, counseling, and family therapies) were added to treatment with either methadone or buprenorphine. The addition of the psychosocial intervention (regardless of the specific psychosocial approach) to the pharmacological treatment significantly reduced dropouts, use of opioids during treatment, use of opioids during follow up, and clinical absences during treatment.^[27]

Pain management

A recent systematic review found that patients with chronic pain (noncancer) who had comorbid substance use disorders are more likely to be prescribed opioids and higher doses of opioid medications compared with patients who do not have a history of substance use disorders despite similar pain outcomes.^[28]

As more patients with opioid addiction receive OAT, physicians will encounter OAT patients with acute pain syndromes. Acute pain must be adequately treated in these patients.^[29]

Common misconceptions include the following:

• OAT provides analgesia: Maintenance methadone or buprenorphine does not provide sustained analgesia. Although methadone and buprenorphine are potent analgesics, the analgesic properties last only 4-8 hours, while the medications are dosed every 24-48 hours.
• Use of opioid analgesia may cause addiction relapse: No evidence indicates that exposure to opioid analgesics during acute pain increases relapse rates. In fact, evidence suggests that the stress of unrelieved pain can trigger relapse.
• The combination of OAT and other opioids may cause respiratory depression: This is a theoretical risk that is not supported by clinical or empirical experience. Tolerance to respiratory and CNS depressant effects occurs rapidly and reliably.

Recommendations include the following:

• Reassure patients that their addiction histories will not prevent adequate pain management, and discuss plans in a nonjudgmental manner.
• Verify methadone and buprenorphine doses with clinics or prescribing physicians, and inform these physicians of any benzodiazepines or opioids given that may be detected on urine drug screening.
• Aggressively treat pain with conventional opioid analgesics. Opioid cross-tolerance often necessitates higher opioid analgesic doses at shorter intervals.
• Use continuous scheduled dosing orders rather than as-needed orders.
• For patients receiving methadone maintenance therapy: Continue methadone maintenance dose and add short-acting opioid analgesics.
• For patients receiving buprenorphine maintenance therapy: Pain management with opioids is complicated by the high affinity of buprenorphine for the mu receptor. This affinity may cause buprenorphine to compete with opioid analgesics at mu receptors. As buprenorphine's rate of dissociation from mu receptors is highly variable, naloxone should be available, and consciousness and respiration should be closely monitored.

Several options are possible, and the most effective approach will be determined with increasing clinical experience:

• Continue BMT and titrate a short-acting opioid analgesic to effect.
• Divide buprenorphine dose to 6-8 hours to take advantage of its short-acting analgesic properties.
• Discontinue BMT, implement opioid analgesia, and restart BMT when opioid analgesia is no longer necessary.
• In the hospitalized patient, discontinue BMT, initiate MMT, and add short-acting opioids to treat pain. Have naloxone at bedside. Convert back to BMT prior to discharge from hospital.