Evidence on Buprenorphine Dose Limits: A Review.

OBJECTIVES: As overdose deaths from fentanyl continue to increase, optimizing use of medications for opioid use disorder has become increasingly important. Buprenorphine is a highly effective medication for reducing the risk of overdose death, but only if a patient remains in treatment. Shared decision making between prescribers and patients is important to establish a dose that meets each patient's treatment needs. However, patients frequently face a dose limit of 16 or 24 mg/d based on dosing guidelines on the Food and Drug Administration's package label. METHODS: This review discusses patient-centered goals and clinical criteria for determining dose adequacy, reviews the history of buprenorphine dose regulation in the United States, examines pharmacological and clinical research results with buprenorphine doses up to 32 mg/d, and evaluates whether diversion concerns justify maintaining a low buprenorphine dose limit. RESULTS: Pharmacological and clinical research results consistently demonstrate buprenorphine's dose-dependent benefits up to at least 32 mg/d, including reductions in withdrawal symptoms, craving, opioid reward, and illicit use while improving retention in care. Diverted buprenorphine is most often used to treat withdrawal symptoms and reduce illicit opioid use when legal access to it is limited. CONCLUSIONS: In light of established research and profound harms from fentanyl, the Food and Drug Administration's current recommendations on target dose and dose limit are outdated and causing harm. An update to the buprenorphine package label with recommended dosing up to 32 mg/d and elimination of the 16 mg/d target dose would improve treatment effectiveness and save lives.

Prescribing the Buprenorphine Monoproduct for Adverse Effects of Buprenorphine-Naloxone.

Buprenorphine-naloxone (BNX) reduces the risk of mortality from untreated opioid use disorder by 50% or more. However, adverse effects of BNX can be a cause of inconsistent use or discontinuation. The buprenorphine monoproduct (BUP) is effective and is sometimes tolerated better, but practice guidelines and insurance restrictions discourage its prescription due to concerns about diversion and injection. An idiopathic reaction of bilateral flank pain reported by three patients is used as an example to show how to assess the success of a BUP trial. Sublingual absorption of naloxone is discussed as a potential cause of adverse effects of BNX in sensitive individuals. Issues in clinical decision-making are presented to help prescribers assess the risk-benefit ratio of a BUP trial for the individual patient, the prescriber, and society. This commentary may serve as a stimulus for changes in practice guidelines and insurance coverage policies to allow greater flexibility in the prescribing of BUP.

Problem Drug-related Behavior and Discontinuation of Opioids Following the Introduction of an Opioid Management Program.

PURPOSE: Problem drug-related behavior (PDB) among patients on chronic opioid therapy may reflect an opioid use disorder. This study assessed PDB prevalence and the relationship between PDB and ongoing prescription of opioids at a primary care clinic that implemented a multifaceted opioid management program. METHODS: A chart review of patients in a chronic opioid registry assessed prevalence of different types of PDB over 2 years, and whether opioids were prescribed during the last 3 months of the 2-year study period among patients with different levels of PDB. RESULTS: Among 233 registry patients, 84.1% exhibited PDB; 45.5% exhibited ≥3 types of PDB. At the end of 2 years, most registry patients were still prescribed opioids, though patients with ≥3 types of PDB were less likely than those without PDB to be prescribed opioids (62.3% vs. 78.4%, P = 0.016). CONCLUSIONS: PDB was pervasive in this population of patients on chronic opioid therapy. Those with the most PDB, and thus with the greatest likelihood of opioid use disorder and its social and medical consequences, were the least likely to be prescribed opioids by the clinic after 2 years. Given the rising rates of illicit opioid use in the U.S., it is important that clinics work closely with their patients who display PDB, systematically assess them for opioid use disorder, and offer evidence-based treatment.

Ultra-low dose ketamine and memantine treatment for pain in an opioid-tolerant oncology patient.

Patients taking high-dose opioids chronically for tumor-related or neuropathic pain may develop pain that is refractory to opioids. One option for control of such pain is the use of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine. We describe a case of opioid-refractory pain that responded to a low-dose IV infusion of ketamine in the inpatient setting. The patient was then successfully transitioned to oral memantine for long-term outpatient management, in a novel use of this oral NMDA receptor antagonist. We present recent findings from basic research on pain mechanisms to explain why opioid tolerance, as in this patient, may contribute to the analgesic benefit of NMDA receptor antagonists.

Recurrent transient global amnesia with intrathecal baclofen.

A middle-aged woman began experiencing spells of profound anterograde amnesia several months after beginning intrathecal baclofen treatment for generalized dystonia. Her spells met criteria for transient global amnesia, but were unusual because of their frequent recurrence and because their frequency was somewhat dose-dependent on baclofen. Fludrocortisone decreased the frequency of these episodes, and sublingual nitroglycerin both prevented and terminated them. Baclofen-induced amnesia in rodents is a reliable model of memory impairment. In contrast, baclofen-induced memory impairment in humans is uncommon. Baclofen- associated transient global amnesia has not previously been reported.

Synaptic depression as a timing device.

A depressing synapse transforms a time interval into a voltage amplitude. The effect of that transformation on the output of the neuron and network depends on the kinetics of synaptic depression and properties of the postsynaptic neuron and network. Using as examples neural circuits that incorporate depressing synapses, we show how short-term depression can contribute to a surprising variety of time-dependent computational and behavioral tasks.

Complex regional pain syndrome as a stress response.

A man in his 50's with a prior traumatic brain injury and multiple psychiatric disorders developed acute pain and swelling in his left leg distal to the mid shin. These symptoms arose during an exacerbation of his post-traumatic stress disorder (PTSD). Among his traumatic memories, he reported having witnessed the combat injury and death of a friend who had lost his left leg distal to the mid shin. A diagnosis of conversion disorder was technically excluded because the findings met criteria for Complex Regional Pain Syndrome (CRPS) type I. Based on recent research into the neurobiology of CRPS, PTSD and conversion disorder, we propose a supraspinal mechanism which could explain how emotional stress can produce both symptoms and signs.

Dynamic influences on coincidence detection in neocortical pyramidal neurons.

The firing rate of neocortical pyramidal neurons is believed to represent primarily the average arrival rate of synaptic inputs; however, it has also been found to vary somewhat depending on the degree of synchrony among synaptic inputs. We investigated the ability of pyramidal neurons to perform coincidence detection, that is, to represent input timing in their firing rate, and explored some factors that influence that representation. We injected computer-generated simulated synaptic inputs into pyramidal neurons during whole-cell recordings, systematically altering the phase delay between two groups of periodic simulated input events. We explored how input intensity, the synaptic time course, inhibitory synaptic conductance, and input jitter influenced the firing rate representation of input timing. In agreement with computer modeling studies, we found that input synchronization increases firing rate when intensity is low but reduces firing rate when intensity is high. At high intensity, the effect of synchrony on firing rate could be switched from reducing to increasing firing rate by shortening the simulated excitatory synaptic time course, adding inhibition (using the dynamic clamp technique), or introducing a small input jitter. These opposite effects of synchrony may serve different computational functions: as a means of increasing firing rate it may be useful for efficient recruitment or for computing a continuous parameter, whereas as a means of decreasing firing rate it may provide gain control, which would allow redundant or excessive input to be ignored. Modulation of dynamic input properties may allow neurons to perform different operations depending on the task at hand.

Synaptic depression in the localization of sound.

Short-term synaptic plasticity, which is common in the central nervous system, may contribute to the signal processing functions of both temporal integration and coincidence detection. For temporal integrators, whose output firng rate depends on a running average of recent synaptic inputs, plasticity modulates input synaptic strength and thus may directly control signalling gain and the function of neural networks. But the firing probability of an ideal coincidence detector would depend on the temporal coincidence of events rather than on the average frequency of synaptic events. Here we have examined a specific case of how synaptic plasticity can affect temporal coincidence detection, by experimentally characterizing synaptic depression at the synapse between neurons in the nucleus magnocellularis and coincidence detection neurons in the nucleus laminaris in the chick auditory brainstem. We combine an empirical description of this depression with a biophysical model of signalling in the nucleus laminaris. The resulting model predicts that synaptic depression provides an adaptive mechanism for preserving interaural time-delay information (a proxy for the location of sound in space) despite the confounding effects of sound-intensity-related information. This mechanism may help nucleus laminaris neurons to pass specific sound localization information to higher processing centres.