Opioid Withdrawal: A New Look at Medication Options
Opioid dose reduction or transition to another opioid therapy often results in uncomfortable signs and symptoms of withdrawal. The severity of these symptoms can fluctuate among patients, even among those with similar body mass index, gender, and dosage.
Several theories have been proposed regarding the contribution of noradrenergic pathways in the expression of opioid withdrawal.1 In the central nervous system, the major clustering of norepinephrine-producing neurons is in the locus coeruleus (LC). Levels of norepinephrine and its metabolites are altered during opioid dependence, resulting in somatic opioid withdrawal symptoms.1
Other studies have suggested that alterations in the density and sensitivity of alpha and beta adrenergic receptors plays a role.1 Still, others suggest that a mesolimbic dopaminergic system contributes to opioid withdrawal symptomatology.2
In October, Practical Pain Management featured an article by Hymes et al on the use of percutaneous electrical neurostimulation to treat withdrawal symptoms.3 In this article, the authors examine pharmaceutical ways to attenuate withdrawal symptoms. By taking advantage of alpha- and beta-agonists and antagonist, clinicians can provide faster tapers and less withdrawal symptoms—without adding a new medication to patients polytherapy.
Symptoms of Opioid Withdrawal
Opioid receptor activation is mediated by 3 different opioid receptors: delta, kappa, and mu. Symptoms of opioid withdrawal may begin 8 to 10 hours after the last dose, depending on the half-life and volume of distribution of the opioid (Table 1). The dosage form and route of administration can influence a drug’s pharmacokinetic parameters and the onset of withdrawal following cessation of the drug.
The majority of opioid withdrawal symptoms reflect increased activity of the autonomic nervous system (ANS). While hyperactivity of noradrenergic neurons within the LC has been associated with somatic symptoms of opioid withdrawal, it is also noteworthy that the LC is involved with various neurophysiologic functions,1 including learning processes and the emotions of anxiety and fear.
For these reasons, it is thought that excessive activation of the LC noradrenergic neurons not only induces somatic symptoms of opioid withdrawal but also causes the cognitive and emotional problems associated with withdrawal.
The initial phase of withdrawal includes acute symptoms such as lacrimation, rhinorrhea, yawning, and sweating that may last 7 to 10 days as well as symptoms that occur later, such as restless sleep, weakness, chills, nausea and vomiting, muscle aches, and involuntary movements. The secondary phase of withdrawal includes symptoms such as hypotension, bradycardia, hypothermia, mydriasis, and decreased responsiveness of the respiratory system to carbon monoxide. The secondary phase can last anywhere from 26 to 30 weeks.4
The Clinical Opioid Withdrawal Scale (COWS) is a tool used by clinicians to assess the degree of withdrawal a patient is experiencing based on current symptoms.5 The COWS reflects the assessment of 11 symptoms:, vital signs (pulse), a brief physical exam (pupil size, sweating, restlessness, runny nose or eye tearing, achiness, GI distress, tremor, yawning, gooseflesh skin) and mental status (irritability or anxiety).5
These symptoms are then converted into a numeric score based on their severity. These numbers are totaled to form an overall score, from 0 (indicating no withdrawal symptoms) to 48 (the maximum degree of withdrawal symptoms). These scores typically are used to determine whether buprenorphine induction is appropriate, with mild to moderate withdrawal symptoms being the ideal time to begin buprenorphine therapy.5
Treatment of Withdrawal
There are myriad agents that can be used to support clinicians in their treatment of patients experiencing opioid withdrawal. The following is a summary of agents that can attenuate withdrawal symptoms (Table 2).
Administration of the alpha-1 antagonists phentolamine,6 phenoxybenzamine (Dibenzyline, others),6 and prazosin (Minpress, others)7 can decrease the occurrence of somatic symptoms associated with opioid withdrawal.
Trazodone (Oleptro, others) is a triazolopyridine derivate that is used as an antidepressant.8 Trazodone acts as a 5-serotonin (HT)2 receptor antagonist at high doses and inhibits the reuptake of serotonin at the presynaptic membrane. Trazodone also weakly inhibits alpha-2 adrenergic receptors and strongly inhibits postsynaptic alpha-1 receptors. Due to its ability to inhibit alpha-1 adrenergic receptors, we postulate that it has a role in opioid withdrawal. Interestingly, trazodone has been shown to bind to opioid receptors as well, but only at high concentrations.8
When studied in mice, trazodone was found to induce potent mu-1 and mu-2 opioid receptor–mediated pain relief. Schreiber et al evaluated the effects of trazodone on opioid withdrawal symptoms in morphine-dependent mice who were receiving a high dose of naloxone.9 They evaluated the intensity of withdrawal symptoms using 3 different behavioral measurements: rearing, jumping, and grooming and found that adding trazodone to naloxone in morphine-dependent mice effectively decreased opioid-withdrawal intensity.9
Another agent that is commonly used to attenuate opioid withdrawal is clonidine (Catapres, Kapvay, others). The use of clonidine for opioid withdrawal originally was proposed by DeStefano et al.10 In addition, studies have revealed that clonidine plays a role in reducing the negative motivational aspects of opioid withdrawal.11
A recent review article by Gowing et al evaluated the evidence for alpha-2 adrenergic agonists in the management of withdrawal symptoms in people who are physically dependent on opioids.12 The review evaluated 25 randomized control trials consisting of 1,668 opioid-dependent patients who were being treated with either clonidine, lofexidine, guanfacine (Tenex, Intuniv, others), or tizanidine (Zanaflex, others). Twelve studies compared alpha-adrenergic agonists with decreasing doses of methadone (Dolophine, Methadose, others), 5 studies compared alpha-2 agonists with placebo, 4 studies compared the study drug with drugs used for specific symptom control in withdrawal, and 5 studies compared different alpha-2 adrenergic agonists to each other. Treatment duration averaged 1 to 2 weeks (shortest duration was 3 days, and longest duration was 30 days).