Understanding Opioid Actions, Pain and Analgesia: A Tribute to Dr. Gavril Pasternak.

This special issue is a tribute to our mentor, colleague and friend, Gavril W. Pasternak, MD, PhD. Homage to the breadth and depth of his work (~ 450 publications) over a 40 career in pharmacology and medicine cannot be captured fully in one special issue, but the 22 papers collected herein represent seven of the topics near and dear to Gav's heart, and the colleagues, friends and mentees who held him near to theirs. The seven themes include: (1) sites and mechanisms of opioid actions in vivo; (2) development of novel analgesic agents; (3) opioid tolerance, withdrawal and addiction: mechanisms and treatment; (4) opioid receptor splice variants; (5) novel research tools and approaches; (6) receptor signaling and crosstalk in vitro; and (7) mentorship. This introduction to the issue summarizes contributions and includes formal and personal remembrances of Gav that illustrate his personality, warmth, and dedication to making a difference in patient care and people's lives.

Six Key Approaches in Open Society Foundations' Support for Global Palliative Care Development.

CONTEXT: Between 1998 and 2021, the Open Society Foundations (OSF) network invested around US$50 million in supporting the emerging field of palliative care worldwide, funding different approaches and interventions to advance its objective of putting palliative care on the global public health agenda. OBJECTIVE: To describe six approaches that were instrumental to the successes of Open Society Foundations' support in building the global field of palliative care. A robust discussion of lessons learnt is unfortunately not possible because Open Society Foundations did not commission a rigorous evaluation of the impacts of its investments. METHODS: This article describes these six approaches: Investing in versatile palliative care leaders at national and regional level; investing in palliative care champions within the OSF network; proactively engaging the World Health Organization (WHO) in efforts to promote palliative care; developing tools and skills to improve palliative care financing; using a human rights-based approach; and supporting self-advocacy by people with palliative care needs. RESULTS: Deep, long-term investments in national and regional champions from the palliative care community and OSF's own network built palliative care leaders with well-rounded skills, knowledge and opportunities to develop their own networks. The active engagement and involvement of the WHO in efforts to advance palliative care enhanced the credibility of palliative care as a discipline as well its champions, whereas the human rights approach resulted in more diverse strategies to overcome barriers to palliative care. The focus on palliative care financing and self-advocacy showed significant promise for impact. DISCUSSION: The approaches and strategies described helped a nascent palliative care field develop into a health service that is increasingly integrated into public health systems. Other funders and national governments can build on OSF's long term support for the palliative care field and support further integration of palliative care within public health to increase access.

How well is cancer pain treated?

There are currently two indicators, Morphine Consumption Data and the Pain Management Index, that have been widely used to assess the efficacy of cancer pain treatment. Both are based on the World Health Organization guidelines for cancer pain and both have limitations in their ability to assess the quality of pain care for cancer patients. The published studies that have used these methods all report that cancer pain is generally undertreated in a wide range of clinical settings and care models.

Types and epidemiology of cancer-related neuropathic pain: the intersection of cancer pain and neuropathic pain.

Neuropathic pain--pain resulting from a lesion, damage, or dysfunction of the somatosensory nervous system--can arise through several distinct etiologies ranging from toxicity, surgery, radiation, and trauma to congenital disorders. Neuropathic pain is widely recognized as a common consequence of cancer and results from administration of several common oncology drugs. It not only impacts quality of life, but it also impacts patient outcomes because of resulting treatment delays, dose reductions, and discontinuations. We estimate that the cost of the problem in the U.S. alone is approximately $2.3 billion. Despite its widely recognized importance, there is a paucity of reliable information available regarding the incidence, prevalence of patient-and physician-reported severity, and time course of cancer-related neuropathic pain. To address this severe knowledge gap, we need new, high-quality, population-based studies of individual cancer pain syndromes and conditions. However, in order to gather this information, we also need substantial improvements in the specific classification of cancer-related neuropathic syndromes and better validated diagnostic tools that can help to elucidate the incidence, prevalence, severity, and potential economic impact of cancer-associated neuropathies.

End of life: Expert care and support, not physician-hastened death.

In legal physician-hastened death, a physician prescribes medication with the primary intent of causing the death of a willing terminally ill patient. This practice differs radically from palliative sedation, intended to relieve a patient's suffering rather than cause a patient's death. In this position paper, we argue that the practice of physician-hastened death is contrary to the interests of patients, their families, and the sound ethical practice of medicine. Therefore, the American Academy of Neurology should advise its members against this practice, as it had done until 2018.

Managing an acute pain crisis in a patient with advanced cancer: "this is as much of a crisis as a code".

The assessment and management of an acute pain crisis in the setting of advanced illness is challenging. Using the case of Mr X, a 33-year-old man with advanced metastatic mucinous adenocarcinoma of the appendix and "15 out of 10" pain, we explore the issues of acute pain and its management. We define a pain crisis as an event in which the patient reports pain that is severe, uncontrolled, and causing distress for the patient, family members, or both. Our management strategy focuses on making a pain diagnosis, differentiating reversible from intractable causes of pain, and making decisions about further workup; selecting the opioid and monitoring and treating opioid adverse effects; titrating and rotating opioid and coanalgesics; consulting experts to treat a pain crisis as quickly as possible to prevent unnecessary suffering; and co-opting the available institutional resources. The timely intervention of a palliative care team and its expertise can provide the staff, patients, and their families the benefit of an interdisciplinary approach and help the patients address goals of care; understand the benefits and risks of treatment decisions; and meet the psychological, social, and existential needs of the patient and the family commonly seen in this setting.

The International Palliative Care Initiative.

This journal series describes the Open Society Foundation's International Palliative Care Initiative (IPCI) and the work of its national, regional, and international foundations and grantees to advance and develop palliative care globally. It provides examples of funding initiatives of IPCI honoring both grass roots and elite strategies of IPCI to integrate palliative care into national and international health policy based on a human rights approach.

World Health Organization Public Health Model: A Roadmap for Palliative Care Development.

The Open Society Foundation's International Palliative Care Initiative (IPCI) began to support palliative care development in Central and Eastern Europe and the Former Soviet Union in 1999. Twenty-five country representatives were invited to discuss the need for palliative care in their countries and to identify key areas that should be addressed to improve the care of adults and children with life-limiting illnesses. As a public health concern, progress in palliative care requires integration into health policy, education and training of health care professionals, availability of essential pain relieving medications, and health care services. IPCI created the Palliative Care Roadmap to serve as a model for government and/or nongovernment organizations to use to frame the necessary elements and steps for palliative care integration. The roadmap includes the creation of multiple Ministry of Health-approved working groups to address: palliative care inclusion in national health policy, legislation, and finance; availability of essential palliative care medications, especially oral opioids; education and training of health care professionals; and the implementation of palliative care services at home or in inpatient settings for adults and children. Each working group is tasked with developing a pathway with multiple signposts as indicators of progress made. The roadmap may be entered at different signposts depending upon the state of palliative care development in the country. The progress of the working groups often takes place simultaneously but at variable rates. Based on our experience, the IPCI Roadmap is one possible framework for palliative care development in resource constrained countries but requires both health care professional engagement and political will for progress to be made.

Leadership Development Initiative: Growing Global Leaders Advancing Palliative Care.

The International Palliative Care Leadership Development Initiative (LDI) was a model demonstration project that aimed to expand the global network of palliative care leaders in low- and moderate-resource countries who are well positioned to apply their new leadership skills. Thirty-nine palliative medicine physicians from 25 countries successfully completed the two-year curriculum that included three thematic residential courses, mentorship, and site visits by senior global palliative care leaders and personal projects to apply their new leadership skills. The focus on self-reflection, leadership behaviors and practices, strategic planning, high-level communication, and teaching skills led to significant personal and professional transformation among the participants, mentors, and the LDI team. The resulting residential course curriculum and the personal leadership stories and biosketches of the leaders are now available open access at IPCRC.net. Already, within their first-year postgraduation, the leaders are using their new leadership skills to grow palliative care capacity through significant changes in policy, improved opioid/other medication availability, new and enhanced educational curricula and continuing education activities, and development/expansion of palliative care programs in their organizations and regions. We are not aware of another palliative care initiative that achieves the global reach and ripple effect that LDI has produced.

The public health strategy for palliative care.

The quality of life of at least 100 million people would have improved--if today's knowledge of palliative care was accessible to everyone. A Public Health Strategy (PHS) offers the best approach for translating new knowledge and skills into evidence-based, cost-effective interventions that can reach everyone in the population. For PHSs to be effective, they must be incorporated by governments into all levels of their health care systems and owned by the community. This strategy will be most effective if it involves the society through collective and social action. The World Health Organization (WHO) pioneered a PHS for integrating palliative care into a country's health care system. It included advice and guidelines to governments on priorities and how to implement both national palliative care programs and national cancer control programs where palliative care will be one of the four key pillars of comprehensive cancer control. The WHO PHS addresses 1) appropriate policies; 2) adequate drug availability; 3) education of policy makers, health care workers, and the public; and 4) implementation of palliative care services at all levels throughout the society. This approach has demonstrated that it provides an effective strategy for integrating/establishing palliative care into a country.

Integrating palliative care into national policies.

Good policies lay the groundwork for an effective health care system and society. They facilitate the implementation of palliative care programs aimed at providing care for all people in need of these services, and they ensure equitable access to affordable medications and therapies. The lack of good policies can lead to unnecessary suffering and costs for patients, families, and society. Three-quarters of cancer patients worldwide are incurable when diagnosed. Because the size of the problem--and the suffering associated with cancer--is enormous, development of a national cancer control policy is an effective point of entry to begin integrating palliative care into a country's health care system. To be comprehensive, every cancer center must include palliative care. Ideally, palliative care is incorporated as a priority within all aspects of each country's national health plan, so that all patients living with or dying from any chronic disease may have their suffering relieved, including children and the elderly. To this end, policies that address essential medicines must include a list of palliative care medications. Supplies of affordable, generic medications that are "equally efficient" must be adequate and available throughout the country wherever patients live (especially opioids for pain control).

Funding for palliative care programs in developing countries.

There are many palliative care developments in resource-poor regions of the world. Most of them are supported by third-party donors and grant makers. The funding necessary to cover essential palliative care services usually exceeds the financial means of many developing countries. Health care services may have to be complemented by nongovernmental organizations that are dependent on fund raising and voluntary donations from a variety of external sources. Coordinated action by international funding agencies is needed to ensure that the world's poorest people have access to essential medications and appropriate palliative care. To this end, international networking in the palliative care field is vital. There are now a number of collaborative networks that make a significant contribution to the development and sustainability of hospice and palliative care across many resource-poor regions of the world.

Chronic use of opioid analgesics in non-malignant pain: report of 38 cases.

Thirty-eight patients maintained on opioid analgesics for non-malignant pain were retrospectively evaluated to determine the indications, course, safety and efficacy of this therapy. Oxycodone was used by 12 patients, methadone by 7, and levorphanol by 5; others were treated with propoxyphene, meperidine, codeine, pentazocine, or some combination of these drugs. Nineteen patients were treated for four or more years at the time of evaluation, while 6 were maintained for more than 7 years. Two-thirds required less than 20 morphine equivalent mg/day and only 4 took more than 40 mg/day. Patients occasionally required escalation of dose and/or hospitalization for exacerbation of pain; doses usually returned to a stable baseline afterward. Twenty-four patients described partial but acceptable or fully adequate relief of pain, while 14 reported inadequate relief. No patient underwent a surgical procedure for pain management while receiving therapy. Few substantial gains in employment or social function could be attributed to the institution of opioid therapy. No toxicity was reported and management became a problem in only 2 patients, both with a history of prior drug abuse. A critical review of patient characteristics, including data from the 16 Personality Factor Questionnaire in 24 patients, the Minnesota Multiphasic Personality Inventory in 23, and detailed psychiatric evaluation in 6, failed to disclose psychological or social variables capable of explaining the success of long-term management. We conclude that opioid maintenance therapy can be a safe, salutary and more humane alternative to the options of surgery or no treatment in those patients with intractable non-malignant pain and no history of drug abuse.

The nature of opioid responsiveness and its implications for neuropathic pain: new hypotheses derived from studies of opioid infusions.

In recent years, the observation that the response of patients to opioid drugs may be influenced by properties inherent in the pain or pain syndrome, such as its pathophysiology, has evolved into the belief that certain types of pain, e.g., neuropathic pains, may be unresponsive to these drugs. This concept has important implications for both clinical practice and basic understanding of opioid mechanisms. We critically evaluate opioid responsiveness, particularly as it relates to neuropathic pain, and propose a clinically relevant definition and a paradigm for its investigation. The paradigm is illustrated by analgesic responses to opioid infusion in 28 patients with neuropathic pains and by a detailed presentation of the pharmacokinetic and pharmacodynamic relationships in one of these patients, whose central pain responded promptly to an infusion of hydromorphone. From this analysis, we hypothesize that (1) opioid responsiveness in man can be defined by the degree of analgesia achieved during dose escalation to either intolerable side effects or the occurrence of 'complete' or 'adequate' analgesia; (2) opioid responsiveness is a continuum, rather than a quantal phenomenon; (3) opioid responsiveness is determined by a diverse group of patient characteristics and pain-related factors, as well as drug-selective effects; and (4) a neuropathic mechanism may reduce opioid responsiveness, but does not result in an inherent resistance to these drugs. Given the complexity of factors contributing to opioid responsiveness and the observation that outcome cannot be reliably predicted, opioids should not be withheld on the assumption that pain mechanism, or any other factor, precludes a favorable response. Both the clinical use of opioids and paradigms to investigate opioid responsiveness should include dose escalation to maximally tolerated levels and repeated monitoring of analgesia and other effects.

The impact of a comprehensive evaluation in the management of cancer pain.

To evaluate the importance of a comprehensive evaluation in the management of patients with cancer pain, we surveyed 276 consecutive consultations (226 retrospectively and 50 prospectively) performed by the pain consultant at Memorial Sloan-Kettering Cancer Center. For all consultations, the pain diagnosis, other medical and neurologic diagnoses, investigations and suggested therapeutic interventions were recorded. The pain consultation identified a previously undiagnosed etiology for the pain in 64% of patients in both surveys. Metastatic neoplasm was the most common lesion discovered. In addition, the prospective survey yielded new neurologic diagnoses in 36% of patients and an unsuspected infection in 4%. Eighteen percent of prospectively surveyed patients received radiotherapy, surgery or chemotherapy based on the findings of the pain consultant. These data confirm the importance of a comprehensive neuro-oncologic evaluation in the management of cancer pain. An understanding of oncology, neurology and medicine is critical to assess and treat these patients.

Clinical analgesic assay of repeated and single doses of heroin and hydromorphone.

A direct comparison of the analgesic activities of heroin and hydromorphone was carried out in cancer patients with postsurgical pain. Intramuscular doses of 5 and 10 mg of heroin were compared with 1 and 2 mg of hydromorphone in a randomized, double-blind, 4-point parallel group assay. Design innovations in the study provided that about half the patients would receive prior repeated doses of the same drug as the test medication, and half would receive the alternate medication. Both test drugs were found to be potent, relatively short acting analgesics with similar profiles of action. Hydromorphone was about 5 times as potent as heroin on a milligram basis. The comparison of those patients who had repeated doses of the same treatment prior to the test dose and those who had repeated doses of the alternate drug demonstrated no significant effect on the relative potency estimates. Side effect occurrence was similar for both drugs, with sleepiness the most prominent effect. The study supports the view that hydromorphone and heroin produce similar clinical effects, and that either drug may adequately substitute for the other. Covariate analysis indicated that time since last analgesic was positively related to analgesia, and amount of prior opioid had a negative relationship. To a lesser extent, increase in patient age was associated with an increase in analgesic scores. Taking these covariates into account served to increase the sensitivity of the analysis.

Dextromethorphan suppresses both formalin-induced nociceptive behavior and the formalin-induced increase in spinal cord c-fos mRNA.

The injection of dilute formalin results in a stereotyped nociceptive behavioral response. Administration of dextromethorphan (s.c.) but not saline, 30 min prior to intraplantar formalin injection prevents this nociceptive response in a dose-dependent manner. In addition, intraplantar formalin reliably induces c-fos mRNA in the ipsilateral spinal dorsal horn as assessed with quantitative solution hybridization at 30 min postinjection. No change in c-fos mRNA was detected in the contralateral spinal dorsal horn, nucleus raphe magnus, periaqueductal grey, medial thalamus, or sensorimotor cortex. Pretreatment with dextromethorphan at 60 mg/kg s.c., 30 min prior to formalin resulted in a suppression of c-fos induction, so that c-fos mRNA levels in the ipsilateral spinal dorsal horn of animals receiving dextromethorphan prior to formalin did not differ from controls. These data indicate that dextromethorphan suppresses formalin nociceptive behavior and one of the biochemical consequences of formalin nociception, i.e., induction of c-fos mRNA.

Plasma morphine and morphine-6-glucuronide during chronic morphine therapy for cancer pain: plasma profiles, steady-state concentrations and the consequences of renal failure.

Morphine-6-glucuronide (M-6-G) is an active metabolite of morphine that may contribute to drug effects. To understand better the relationship between morphine and M-6-G in cancer patients receiving chronic therapy, we employed high performance liquid chromatography with electrochemical detection to measure: (1) morphine and M-6-G plasma concentrations following discontinuation of dosing in 2 patients, one receiving oral therapy and the other an intravenous infusion; (2) morphine and M-6-G concentrations in random blood samples taken at apparent steady state from 8 patients, 7 with normal renal function and 1 with mild renal insufficiency, who were receiving continuous morphine infusions; and (3) morphine and M-6-G concentrations in random blood samples taken over a period of weeks from 4 patients, 2 with stable and 2 with declining renal function. Results demonstrated a slightly slower decline in plasma M-6-G than morphine concentrations following drug discontinuation, as would be expected for metabolite and parent relationship; roughly similar M-6-G: morphine ratios (mean molar ratio = 1.22) across a broad range of morphine doses in patients with normal renal function; and an increase in this ratio over time in patients with progressive renal dysfunction. These data illustrate the kinetics of M-6-G in cancer patients receiving chronic morphine therapy and confirm the importance of renal function in determining the concentration of the metabolite.