New directions in the treatment of opioid withdrawal

Abstract

The treatment of opioid withdrawal is an important area of clinical concern when treating patients with chronic, non-cancer pain, patients with active opioid use disorder, and patients receiving medication for opioid use disorder. Current standards of care for medically supervised withdrawal include treatment with μ-opioid receptor agonists, (eg, methadone), partial agonists (eg, buprenorphine), and α2-adrenergic receptor agonists (eg, clonidine and lofexidine). Newer agents likewise exploit these pharmacological mechanisms, including tramadol (μ-opioid receptor agonism) and tizanidine (α2 agonism). Areas for future research include managing withdrawal in the context of stabilising patients with opioid use disorder to extended-release naltrexone, transitioning patients with opioid use disorder from methadone to buprenorphine, and tapering opioids in patients with chronic, non-cancer pain.

Figure 1:. Pharmacological mechanisms of agents used in the treatment of opioid withdrawal

Acute opioid binding to the μ-opioid receptor inhibits the downstream cAMP (A), which recovers with chronic opioid use and further increases in withdrawal, leading to excess NE discharge from the noradrenergic neurons in the locus coeruleus (B). Therefore, treatment of withdrawal involves either attenuating the cAMP pathway through μ-opioid receptor agonism (A) or inhibiting excess NE discharge from locus coeruleus neurons through presynaptic α2-receptor agonism. ATP=adenosine triphosphate. cAMP=cyclic adenosine monophosphate. PKA=protein kinase A. NE=norepinephrine. *Not approved by the US Food and Drug Administration yet.

Figure 2:. Algorithm for the treatment of medically supervised opioid withdrawal

CNCP=chronic, non-cancer pain. MOUD=medications for opioid use disorder.