Lofexidine is an alpha₂-adrenergic agonist used to manage the symptoms of opioid withdrawal. It decreases sympathetic nervous system activity which causes many of the withdrawal symptoms.^14,15

One of its sites of action is alpha₂ receptors in the medulla oblongata, the part of the CNS connecting the brainstem to the spinal cord. This carries a number of autonomic nervous system functional centres associated with respiration, reflexes, blood pressure regulation and several of the cranial nerves.^14,16

A key component of opioid withdrawal is increased central noradrenergic activity. This can be damped down by lofexidine which inhibits adenyl cyclase, causing a fall in cyclic adenosine monophosphate (cAMP) levels in cells, reducing nerve firing. This reduces noradrenergic or sympathetic effects with a reduction in withdrawal symptoms.¹⁴

Clonidine has a similar structure and efficacy to lofexidine but is not recommended for opioid withdrawal due to clonidine being more hypotensive and more likely to cause dizziness.¹⁷