Drug Treatment of Withdrawal Syndromes

Drug Treatment of Withdrawal Syndromes

Some general principles apply to drug treatments for specific withdrawal syndromes:

When monitoring treatment:

·                 Set clear targets.

·                 Make serial assessments and modify based on these assessments.

Psychosocial factors:

·                 Prepare the patient.

·                 Emphasis on detoxification as a beginning to treatment.

From a pharmacologic standpoint, an ideal agent for the treat-ment of withdrawal should have the following characteristics:

·                 Efficacy in relieving the complete range of abstinence signs and symptoms for a given type of withdrawal.

·                 A relatively long duration of action and gradual offset of effects.

·                 A high degree of safety in the dosage needed to suppress with-drawal (i.e., high therapeutic index).

·                 It should be available by a variety of routes of administration and have little abuse potential in itself.

Other general but important aspects of detoxification are also fre-quently overlooked:

·                 Clear treatment targets should be kept in mind.

·                 Structured rating scales should be used to measure symptom severity: serial assessment of the clinical response is the best strategy for guiding treatment and detoxification should not be conducted “on autopilot”.

·                 While protocols may offer useful guidance, orders should be rewritten with thought and often daily.

Patients must understand that detoxification is not a treatment for addiction but the beginning of treatment for the chronic problems associated with substance dependence. They should know what they will experience and they should if at all possible be engaged in the effort to relieve their symptoms as safely as possible and with greatest effectiveness. They need to understand, however, that they are likely to experience some distress. Detoxification can be carried out on an outpatient basis for patients who are in relatively good health and have sufficiently stable social support.

Alcohol Withdrawal

Alcohol withdrawal is a medical emergency and can be life-threatening without appropriate supportive medical treatment.

The risk of progressing from uncomplicated withdrawal to seizures or delirium should be greatly reduced by proper man-agement. Patients should be assessed systematically when enter-ing the detoxification protocol and during the process. A widely used but simple tool is the Clinical Institute Withdrawal Assess-ment – Alcohol Scale (Table 84.1). Starting 6–24 hours after the last drink, this scale should be used to assess the patient initially every 1–2 hours and at regular intervals until two consecutive scores below 8–10 are achieved. It is then safe to end structured assessment. Scores greater than 15 are an indication for monitor-ing the patient even more closely. Scores in between these limits should be interpreted according to clinical judgment according to the degree of discomfort reported by the patient and their history of withdrawal syndromes.

Undertreatment with doses that are too low or dose inter-vals that are too long is the commonest error in the drug treat-ment of withdrawal syndromes. However, striking the balance between withdrawal and intoxication is not complicated provided serial assessments are made.

Benzodiazepines are the drugs of choice for treating alco-hol withdrawal because:

·                 There is cross-tolerance with alcohol (therefore higher than normal doses may be needed).

·                 They are relatively safe compared with other sedative-hypnotics.

·                 They have been shown to reduce the frequency of seizures and delirium.

The benzodiazepines can be divided into two major classes according their duration of action. Longer-acting agents, includ-ing chlordiazepoxide and diazepam, undergo metabolic oxidation and glucuronidation. Their advantage is that blood levels decline more slowly during the tapering process, increasing patient com-fort and reducing the risk of seizures. The disadvantage is that, in older patients and patients with impaired hepatic or pulmonary function, decreased elimination may result in accumulation and toxicity. Chlordiazepoxide may be preferred to diazepam because it may have a lower abuse potential.

Shorter-acting agents, such as oxazepam and lorazepam, are metabolized only by glucuronidation. Both drugs are available in oral and intravenous forms though only lorazepam may also be administered by intramuscular injection. These agents are more readily metabolized and eliminated by older patients and they are less likely to accumulate and cause toxicity in patients with liver disease. However, blood levels decline more rapidly and this may cause breakthrough symptoms and seizures between doses.

The treatment response should be assessed serially. Medi-cation should adjusted according to clinical need: if signs of

withdrawal are apparent, the dose should be increased or the dose interval reduced. Some degree of sedation is desirable but medi-cation should be withheld if the patient becomes over-sedated and recommenced when clinically indicated. Recommendations for medication are summarized in Figure 84.1.

Hallucinations that develop as a feature of delirium are relatively refractory to treatment with a benzodiazepine alone. Patients who develop hallucinations despite sedative-hypnotic substitution may be treated with adjunctive haloperidol, 2 to 5 mg.

In the event of persistent tachycardia or hypertension, the possibility of inadequately treated withdrawal should first be ex-cluded. This problem has been managed successfully with beta-blockers and clonidine but while these agents may decrease vital signs and tremor they do not prevent seizures.

An alternative strategy is to “frontload” the patient, achieving sedation by administering diazepam or chlordiazepox-ide every 1 to 2 hours. Because these agents have a long elimina-tion half-life, their effects diminish slowly and smoothly over the withdrawal period. However, careful serial assessment remains essential while the patient is vulnerable to the complications of withdrawal.

Thiamine is indicated for every patient with alcoholism to prevent Wernicke’s encephalopathy and Korsakoff’s amnestic syndrome. It should be administered immediately (typical dose 100 mg daily), before intravenous glucose. Less urgently, nutri-tional support should include supplementation with folate 1 mg and multivitamins. It has been suggested that magnesium sup-plementation may prevent withdrawal seizures but there is no consensus on its use in the absence of documented magnesium deficiency.

There are promising reports on the use of carbamazepine and valproate in alcohol withdrawal and they may be helpful in special circumstances. However, the safety and efficacy of ben-zodiazepines are currently unsurpassed.

Sedative-hypnotic Withdrawal

Similar to the treatment for alcohol withdrawal, benzodiazepine taper (as described above) is a good choice, particularly if the patients is dependent on benzodiazepines. Another excellent choice for substitution therapy is phenobarbital: it has low po-tential for abuse, there is a wide margin between therapeutic and lethal blood levels, and it has a long duration of action with rela-tively little variation in between-dose blood levels. The symp-toms of intoxication with phenobarbital (ataxia, slurred speech, nystagmus) are readily observed easy and managed within a de-toxication protocol.

For patients dependent on sedative-hypnotics, the first step in management if to take a history. Information about the level of drug consumption can be converted to “phenobarbital equiva-lents” to provide a guide to the required dose of phenobarbital, as specified in Table 84.2.

The number of phenobarbital equivalents is summed and administered as a thrice-daily dose regimen. The total daily requirement of phenobarbital rarely exceeds 500 mg even in patients with extreme dependency. The first dose of phenobarbital may be administered as an intramuscular injec-tion if signs of withdrawal occur before substitution therapy begins. Symptoms of withdrawal and intoxication should be reassessed after 1 to 2 hours to determine the next dose of phenobarbital.

The degree of dependence can also be assessed by serial challenge with pentobarbital at doses of 200 mg but it is not clear that this method offers any advantage over direct substitution with phenobarbital, which is safe, rapid and simple.

There should be no signs of sedative-hypnotic withdrawal or phenobarbital toxicity after 24 to 48 hours; dose reduction of phenobarbital can then be started. Maintaining the thrice-daily dose regimen, the dose of phenobarbital should be reduced in increments of 30 mg/day. If there is evidence of phenobarbital toxicity (slurred speech, nystagmus, ataxia), the next dose should be withheld and the total daily dose reduced. Conversely, if there are objective signs of withdrawal, the total daily dose of pheno-barbital should be increased and dose reduction delayed until the patient is once again stable.

Opiate Withdrawal

Withdrawal from opiates may be intensely uncomfortable but, by contrast with sedative-hypnotic withdrawal, it is not usually life-threatening for adults; important exceptions include adults with little reserve – for example, due to to advanced AIDS – and newborn infants. Nevertheless, reducing withdrawal symptoms may help to engage an addict in a treatment program or facilitate the management of another medical condition.

Methadone is approved by the FDA for treating opiate withdrawal but states may have different regulations governing its use and clinicians need to be aware of local requirements. Methadone use is typically permitted for inpatient detoxification or maintenance treatment but it cannot be prescribed to treat opi-ate withdrawal in outpatients except as part of a licensed metha-done maintenance treatment program.

Methadone is administered orally and has a long duration of action. An initial dose of 15 to 20 mg may be given when signs of opiate withdrawal are seen (not merely when craving is re-ported). An additional 5 to 10 mg may be given in 1 to 2 hours if symptoms persist or worsen. A dose of 40 mg/day usually con-trols signs of withdrawal well (note that this is often insufficient for the different indication of long-term maintenance). If oral ad-ministration is impossible due to withdrawal symptoms, doses of 5 mg may be administered by intramuscular injection. Having reached a dose at which withdrawal symptoms are alleviated, the dose can be tapered by 5 to 10% per day until full detoxification is achieved.

A newly available option for treatment of opioid with-drawal is the Schedule III opioid partial agonist buprenorphine, which is now available for use in the office based practice by any physician who has taken a brief training and certification. While the use of Schedule II drugs such as methadone for the treat-ment for opiate dependence is restricted to hospitals or specially licensed clinics (leading to a shortage of facilities where opiate-dependent individuals could receive appropriate treatment), the Drug Addiction Treatment Act of 2000 introduced less stringent regulations, allowing the use of narcotic drugs for the treatment of addiction in the office or any other health care setting by any licensed physician who has taken a brief training course and obtained registration, thereby increasing access to treatment. Two new formulations of the buprenorphine (Subutex and Sub-oxone sublingual tablets) were the first products to be approved by the FDA under this Act for the treatment of opioid depend-ence. Subutex contains only buprenorphine in doses of 2 or 8 mg; Suboxone also contains the opioid antagonist naloxone (0.5 and 2 mg respectively); the purpose of the naloxone is to discourage diversion of the medication for abuse intravenously (crushing the pills and injecting them), since naloxone is poorly absorbed after oral or sublingual administration, but if injected would produce precipitated withdrawal.

Buprenorphine is an excellent detoxification agent because of its long duration of action, due to very high affinity for and very slow dissociation from opioid receptors. Starting buprenorphine must be done carefully, because of the partial agonism. If admin-istered too close in time to the last dose of a full agonist such as heroin, buprenorphine will precipitate withdrawal, and the with-drawal produced can be atypical and in rare cases has been ob-served to include delirium. Precipitated withdrawal is more likely among patients dependent on long-acting agonists (e.g. metha-done), or high daily doses of a shorter-acting agonist such as heroin. Thus, when starting buprenorphine, the clinician should wait for symptoms of opioid withdrawal to begin to appear before giving the first dose of buprenorphine, which should be a test dose of 2 mg (Subutex 2 mg, or Suboxone (2 mg buprenorphine/0.5 mg naloxone). If this dose is well tolerated, administer another 2 mg one hour later, and up to 8 mg total on the first day, and up to 16 mg on the second day. After this buprenorphine can be tapered slowly to zero over 10 days to 2 weeks. Considerable flexibility in the taper schedule is possible, including a much faster taper, since the slow dissociation from receptors in itself effectively produces a taper. However, clinicians should also be alert for the emergence of low-grade withdrawal symptoms (fatigue, anxiety, mild flu-like physical symptoms) in the weeks after discontinuing buprenor-phine. This subacute or protracted withdrawal can be observed after withdrawal from any opioid drug, but can seem surprisingly with buprenorphine because the taper phase of a buprenorphine detoxification is usually comfortable and uneventful.

If one of the first few doses of buprenorphine administered is followed by a rapid worsening of withdrawal symptoms, this is precipitated withdrawal, and no further buprenorphine should be given; at this point it is probably best to treat with a full agonist (methadone), although one could also wait for precipitated with-drawal to clear and full-blown opiate withdrawal (from whatever the patient was addicted to) to emerge, after which one can try again beginning with a test dose of 2 mg buprenorhine.

A number of nonnarcotic medications are useful in treat-ing the symptoms of opiate withdrawal. These include the α-adrenergic receptor agonist and antihypertensive clonidine, which is particularly helpful with the autonomic symptoms of withdrawal as well as the anxiety, benzodiazepines (clonazepam is typically used), which are particularly helpful for the anxi-ety and insomnia, antiemetics and NSAIDs for muscle aches (oral agents such as ibuprofen, or Toradol which can be given parenterally). Autonomic symptoms may be well controlled with clonidine alone but patients frequently report greater subjective distress than with methadone or buprenorphine. The role of cloni-dine is for detoxification from illegal opiates, for example in set-tings where methadone is not allowed, or to alleviate abstinence symptoms when a patient comes to the end of a methadone main-tenance program. Its major side effects are hypotension (which may require dose reduction or discontinuation) and sedation. Hypotension may be worsened by diarrhea, or vomiting, which are common in opiate withdrawal. Patients should be encouraged to take plenty of fluids, and sports drinks such as gatorade are particularly helpful because they also supply electrolytes. Clo-nidine does not address all aspects of withdrawal and it should therefore be used in combination with the alternatives detailed above. A protocol for clonidine-assisted detoxication is given in Table 84.3.

A combination of clonidine with naltrexone has been used to achieve a more rapid withdrawal, followed by maintenance treatment with naltrexone. However, clinical experience and close monitoring of the patient is necessary to titrate the dose of clonidine against withdrawal symptoms induced by naltrexone. The acceptability of maintenance treatment with naltrexone to opiate addicts is disappointing.

With opiate detoxification, it is particularly important to consider the indications for it, and to establish an adequate treatment plan after detoxification is completed. Chronic opioid use induces tolerance, and detoxification reduces or eliminates tolerance. Because of the loss of tolerance, detoxified opiate ad-dicts are at increased risk for death from opiate overdose; doses that they routine self-administered previously when tolerant, could now be lethal, a problem exacerbated by the variable and sometimes high potency of illicit heroin. In general, the risk of re-lapse following opioid detoxification is high. Therefore, patients should be assessed for overdose risk, and those with a history of past overdoses, or with multiple past relapses, should be encour-aged to take agonist maintenance treatment, with methadone or buprenorphine, rather than undergoing detoxification. For those not entering agonist maintenance, a strong plan for psychosocial treatment is important, for example long-term residential treat-ment or Therapeutic Community, a good outpatient treatment program, supplemented by self-help group (Alcoholics Anony-mous, or Narcotics Anonymous).