Naldemedine-induced opioid withdrawal syndrome with severe psychiatric symptoms in an advanced cervical cancer patient without brain metastasis

Objective Naldemedine, an oral peripheral μ-opioid receptor antagonist, was developed for the treatment of constipation, a side effect of opioid use. Naldemedine is not generally recognized as causing opioid withdrawal in which associated symptoms affecting the central nervous system. Method From the series of cancer patients undergoing symptom management, we report a case treated with naldemedine for constipation in relation to the use of opioids for cancer pain and who displayed severe psychological symptoms associated with withdrawal immediately after the use of naldemedine. Results The patient was a 36-year-old woman diagnosed with cervical cancer Stage IIB, PS3. When the patient, who was using oxycodone hydrochloride hydrate (80 mg/day) for ileal pain, was started on naldemedine for constipation, she complained of sweating after just 5 min and hallucinations after 1 h. The patient also displayed physical/behavioral abnormalities such as diarrhea and hyperactivity, and psychological abnormalities such as aggression toward staff. Despite the psychiatric symptoms worsening over time, there were no abnormalities in terms of blood biochemical data, and no brain metastasis was observed on MRI. Based on the Clinical Opiate Withdrawal Scale, these symptoms were judged to indicate opioid withdrawal. Naldemedine was discontinued due to naldemedine-related opioid withdrawal syndrome and, thereafter, the psychiatric symptoms diminished, with no recurrence of similar symptoms observed to date. Significance of results If mental and behavioral abnormalities occur in patients receiving naldemedine, it is necessary to consider the possibility of opioid withdrawal syndrome as a differential diagnosis.

Opioid withdrawal abruptly disrupts amygdala circuit function by reducing peptide actions

Opioid withdrawal drives relapse and contributes to compulsive drug use through disruption of endogenous opioid dependent learning circuits in the amygdala. Normally, endogenous opioids control these circuits by inhibiting glutamate release from basolateral amygdala principal neurons onto GABAergic intercalated cells. Using patch-clamp electrophysiology in rat brain slices, we reveal that opioid withdrawal dials down this endogenous opioid inhibition of synaptic transmission. Peptide activity is dialled down due to a protein kinase A dependent increase in the activity of the peptidase, neprilysin. This disrupts peptidergic control of both GABAergic and glutamatergic transmission through multiple amygdala circuits, including reward-related outputs to the nucleus accumbens. This likely disrupts peptide-dependent learning processes in the amygdala during withdrawal. and may direct behaviour towards compulsive drug use. Restoration of endogenous peptide activity during withdrawal may be a viable option to normalise synaptic transmission in the amygdala and restore normal reward learning.

Methadone initiation in a bridge clinic for opioid withdrawal and opioid treatment program linkage: a case report applying the 72-hour rule

Background In the United States, methadone for opioid use disorder (OUD) is limited to highly regulated opioid treatment programs (OTPs), rendering it inaccessible to many patients. The “72-hour rule” allows non-OTP providers to administer methadone for emergency opioid withdrawal management while arranging ongoing care. Low-barrier substance use disorder (SUD) bridge clinics provide rapid access to buprenorphine but offer an opportunity to treat acute opioid withdrawal while facilitating OTP linkage. We describe the case of a patient with OUD who received methadone for opioid withdrawal in a bridge clinic and linked to an OTP within 72 h. Case presentation A 54-year-old woman with severe OUD was seen in a SUD bridge clinic requesting OTP linkage and assessed with a clinical opiate withdrawal scale (COWS) score of 12. She reported daily nasal use of 1 g heroin/fentanyl. Prior OUD treatment included buprenorphine-naloxone, which was only partially effective. Her acute opioid withdrawal was treated with a single observed oral dose of methadone 20 mg. She returned the following day with persistent opioid withdrawal (COWS score 11) and was treated with methadone 40 mg. On day 3, the patient was successfully admitted to a local OTP, where she remained engaged 3 months later. Conclusions While patients continue to face substantial access barriers, bridge clinics can play an important role in treating opioid withdrawal, building partnerships with OTPs to initiate methadone on demand, and preventing life-threatening delays to methadone treatment. Federal policy reform is urgently needed to make methadone more accessible to people with OUD.