Opioids and pituitary function: expert opinion.

PURPOSE: Opioids are highly addictive potent analgesics and anti-allodynics whose use has dramatically increased in recent decades. The precipitous rise in opioid dependency and opioid use disorder is an important public health challenge given the risks for severely adverse health outcomes. The long-term opioid impact on hypothalamic-pituitary axes is particularly underappreciated among both endocrinologists and primary care physicians. We review the effects of opioids on hypothalamic-pituitary-target gland function and their implications for clinical practice. METHODS: Experts in hypothalamic-pituitary disorders and opioid pharmacology reviewed recently published literature and considered strategies for diagnosing and managing these opioid-induced endocrine effects. RESULTS: Opioid suppression of hypothalamic-pituitary axes can lead to hypogonadotropic hypogonadism, central adrenal insufficiency, and hyperprolactinemia. These important clinical manifestations are often under-estimated, poorly evaluated, and typically either untreated or not optimally managed. Data on biochemical testing for diagnosis and on the effect of hormone replacement in these patients is limited and prospective randomized controlled studies for guiding clinical practice are lacking. CONCLUSIONS: Patients should be informed about risks for hypogonadism, adrenal insufficiency, and hyperprolactinemia, and encouraged to report associated symptoms. Based on currently available evidence, we recommend clinical and biochemical evaluation for potential central adrenal insufficiency, central hypogonadism, and/or hyperprolactinemia in patients chronically treated with opioids as well as the use of current expert guidelines for the diagnosis and treatment of these conditions.

Opioids and Immunosuppression: Clinical Evidence, Mechanisms of Action, and Potential Therapies.

Background: In addition to the more well-known adverse effects of opioids, such as constipation, mounting evidence supports underlying immunosuppressive effects as well. Methods: In this study, we provide a narrative review of preclinical and clinical evidence of opioid suppression of the immune system as well as possible considerations for therapies. Results: In vitro and animal studies have shown clear effects of opioids on inflammatory cytokine expression, immune cell activity, and pathogen susceptibility. Observational data in humans have so far supported preclinical findings, with multiple reports of increased rates of infections in various settings of opioid use. However, the extent to which this risk is due to the impact of opioids on the immune system compared with other risk factors associated with opioid use remains uncertain. Considering the data showing immunosuppression and increased risk of infection with opioid use, measures are needed to mitigate this risk in patients who require ongoing treatment with opioids. In preclinical studies, administration of opioid receptor antagonists blocked the immunomodulatory effects of opioids. Conclusions: As selective antagonists of peripheral opioid receptors, peripherally acting mu-opioid receptor (MOR) antagonists may be able to protect against immune impairment while still allowing for opioid analgesia. Future research is warranted to further investigate the relationship between opioids and infection risk as well as the potential application of peripherally acting MOR antagonists to counteract these risks.

A Survey on Opioid Tapering Practices, Policies, and Perspectives by Pain and Palliative Care Pharmacists.

Opioid tapering is an essential clinical tool to utilize for a variety of reasons, including safety and analgesic optimization. The need for individualized regimens reveals a corresponding need for healthcare providers who can actively manage patients throughout the process. Pharmacists have taken on an integral role for achieving success in opioid tapering. This survey was conducted to describe the current opioid tapering practices of pain and palliative care pharmacists. A Qualtrics survey was offered to the Society of Pain and Palliative Care Pharmacist members. The majority (87%) indicated they specialized in pain management. Almost all respondents (98%) reported providing tapering recommendations and 82% reported being involved with patient monitoring throughout the taper. The majority (multiple responses could be chosen) noted that the indication for initiating an opioid taper was due to abuse/misuse (91%), reduced overall efficacy (89%), and adverse drug reactions (78%). The most common follow-up intervals during tapering were weekly (15%), every 2 weeks (22%), and every 4 weeks (44%). This practice-based survey, though small, showed that pharmacists in pain management and palliative care are actively involved in opioid tapering. This survey will hopefully serve as a foundation for continuing research into opioid tapering and the pharmacist's role therein.

Emerging pharmacologic mechanisms of buprenorphine to explain experience of analgesia versus adverse effects.

Buprenorphine's unique pharmacologic mechanisms of action lend itself to a higher level of complexity than its typical characterization as a partial agonist at µ-opioid receptors. It is well-documented that its additional activity at Δ- and κ-opioid receptors, and opioid receptor ligand 1 may be associated with varying degrees of analgesia and usual opioid-related adverse effects. However, novel downstream molecular and cellular mechanisms from µ-opioid receptor activation contain potential new insights into its overall unique effects. These include buprenorphine's peculiar ability to induce analgesia at escalating doses, while exhibiting a plateaued effect on respiratory depression, euphoria, gastrointestinal (GI) motility, depression, anxiety, and addictive potential. Thus, this review aims to discuss several of these emerging mechanisms to gain a better understanding of these curious actions, as well as support much of this in vitro evidence with various human clinical trial data to further support buprenorphine's place on the analgesic ladder.

Opioid Taper Practices Among Clinicians.

INTRODUCTION: Opioid dose tapers are used frequently when cross-titrating from one or more opioids to another or when discontinuing therapy. Currently, there is no universally accepted evidence-based standard of care for this procedure which can leave patients at risk for withdrawal symptoms, inadequate pain control, or elevated suicide risk. OBJECTIVE: The objective of this study was to examine practices and rationale among clinicians, to determine if there is a difference among respondents in their comfort level, method and rationale for tapering opioids at various morphine milligram equivalents (MME) and to assess the need for the development of a standard of care. METHODS: Data were derived from an electronic survey developed using SurveyMonkey®. The survey was disseminated via e-mail listservs, social media, and professional organizations. Data were collected regarding profession, confidence tapering opioids at varying total MME, method and rationale for tapering, and pharmacologic management of withdrawal symptoms. Pearson's Chi squared and Fisher's exact tests were used to assess statistical significance of results. RESULTS: A total of 149 clinicians completed the survey, physicians, NPs, pharmacists, and PAs accounted for 51%, 20%, 19%, and 10% of participants, respectively. Overall, 55% of the respondents self-identified as pain specialists. There were no statistically significant differences in reported comfort level among the different types of providers. Nearly 50% of participants indicated their rationale for tapering or discontinuing opioids was the 2016 CDC guidelines. CONCLUSION: Despite that the majority of providers surveyed self-identified as pain specialists, over 50% were not comfortable tapering opioids at doses greater than 120 MME/day. This observation suggests a need for further education and establishment of consensus guidelines on method and rationale for opioid tapering. Provider motivation for tapering was largely influenced by CDC guidelines based on low quality evidence. This strengthens the argument for the creation of guidelines based on high quality evidence.

Amid COVID-19 crisis, pain therapeutics telehealth services by pharmacist clinicians fill unique void and mitigate risk.

Patients with chronic pain syndromes are facing additional challenges from syndrome coronavirus 2 (SARS-CoV-2) virus compared with the general population. New reasons for compounded social isolation and commensurate opioid dose creeping and suicidality/anxiety, difficulty in obtaining legitimate medications, proper comprehensive evaluations, ongoing opioid risk stratification for opioid abuse/misuse, safe opioid tapers if necessary, and other opportunities for pharmacist intervention are clear. We discuss opportunities for pharmacist-run telehealth visits, reimbursement for services, and various aspects of interventions during this time of international emergency where all healthcare professionals have been asked to step up to help combat the mutual threat of COVID19. Clinical pharmacists in every specialty area are part of the essential healthcare workforce, but those practicing pain management in particular are in unique positions to assist all providers in adhering to chronic pain guidelines and various government mandates, and to foster optimal outcomes to complex patients with chronic pain. Furthermore, those that are available by telemedicine allow for improved access to quality and appropriate pain medication management, and additionally support opioid risk mitigation strategies, helping fill an unmet access to those at higher risk. This practice has the potential to help offset primary care provider workload, allowing for a decreased overall burden, especially in a complex, time-consuming, and high-risk patient population.

Pharmacotherapeutic Management of Neuropathic Pain in End-Stage Renal Disease.

BACKGROUND: Chronic noncancer pain is pervasive throughout the general patient population, transcending all chronic disease states. Patients with end-stage renal disease (ESRD) present a complicated population for which medication management requires careful consideration of the pathogenesis of ESRD and intimate knowledge of pharmacology. The origin of pain must also guide treatment options. As such, the presentation of neuropathic pain in ESRD can present a challenging case. The authors aim to provide a review of available classes of medications and considerations for the treatment of neuropathic pain in ESRD. SUMMARY: In this narrative review, the authors discuss important strategies and considerations for the treatment of neuropathic pain in ESRD, including the pathogenesis of neuropathic pain, physiological changes for consideration in ESRD patients, and disease-specific consideration for medication selection. Pharmacotherapeutic classes discussed include: anticonvulsants, antiarrhythmics, antidepressants, topicals, and opioids. KEY MESSAGE: Pain management in ESRD patients requires careful assessment of drug-specific properties, accumulation, metabolism (presence of active/toxic metabolites), extraction by dialysis, and presence of drug - drug interactions. In the absence of pharmacokinetic data in ESRD patients, therapeutic window and potential risks should be factored in the decision making along with continued monitoring throughout therapy.

A Practical Guide to Urine Drug Monitoring.

Urine drug monitoring is an important tool for substance misuse or abuse and adherence to a prescribed regimen.

In silico ordinary differential equation/partial differential equation hemodialysis model estimates methadone removal during dialysis.

BACKGROUND: There is a need to have a model to study methadone's losses during hemodialysis to provide informed methadone dose recommendations for the practitioner. AIM: To build a one-dimensional (1-D), hollow-fiber geometry, ordinary differential equation (ODE) and partial differential equation (PDE) countercurrent hemodialyzer model (ODE/PDE model). METHODOLOGY: We conducted a cross-sectional study in silico that evaluated eleven hemodialysis patients. Patients received a ceiling dose of methadone hydrochloride 30 mg/day. Outcome measures included: the total amount of methadone removed during dialysis; methadone's overall intradialytic mass transfer rate coefficient, km ; and, methadone's removal rate, j ME. Each metric was measured at dialysate flow rates of 250 mL/min and 800 mL/min. RESULTS: The ODE/PDE model revealed a significant increase in the change of methadone's mass transfer with increased dialysate flow rate, %Δkm =18.56, P=0.02, N=11. The total amount of methadone mass transferred across the dialyzer membrane with high dialysate flow rate significantly increased (0.042±0.016 versus 0.052±0.019 mg/kg, P=0.02, N=11). This was accompanied by a small significant increase in methadone's mass transfer rate (0.113±0.002 versus 0.014±0.002 mg/kg/h, P=0.02, N=11). The ODE/PDE model accurately predicted methadone's removal during dialysis. The absolute value of the prediction errors for methadone's extraction and throughput were less than 2%. CONCLUSION: ODE/PDE modeling of methadone's hemodialysis is a new approach to study methadone's removal, in particular, and opioid removal, in general, in patients with end-stage renal disease on hemodialysis. ODE/PDE modeling accurately quantified the fundamental phenomena of methadone's mass transfer during hemodialysis. This methodology may lead to development of optimally designed intradialytic opioid treatment protocols, and allow dynamic monitoring of outflow plasma opioid concentrations for model predictive control during dialysis in humans.