Opioid analgesics for nociceptive cancer pain: A comprehensive review.

Pain is one of the most burdensome symptoms in people with cancer, and opioid analgesics are considered the mainstay of cancer pain management. For this review, the authors evaluated the efficacy and toxicities of opioid analgesics compared with placebo, other opioids, nonopioid analgesics, and nonpharmacologic treatments for background cancer pain (continuous and relatively constant pain present at rest), and breakthrough cancer pain (transient exacerbation of pain despite stable and adequately controlled background pain). They found a paucity of placebo-controlled trials for background cancer pain, although tapentadol or codeine may be more efficacious than placebo (moderate-certainty to low-certainty evidence). Nonsteroidal anti-inflammatory drugs including aspirin, piroxicam, diclofenac, ketorolac, and the antidepressant medicine imipramine, may be at least as efficacious as opioids for moderate-to-severe background cancer pain. For breakthrough cancer pain, oral transmucosal, buccal, sublingual, or intranasal fentanyl preparations were identified as more efficacious than placebo but were more commonly associated with toxicities, including constipation and nausea. Despite being recommended worldwide for the treatment of cancer pain, morphine was generally not superior to other opioids, nor did it have a more favorable toxicity profile. The interpretation of study results, however, was complicated by the heterogeneity in the study populations evaluated. Given the limited quality and quantity of research, there is a need to reappraise the clinical utility of opioids in people with cancer pain, particularly those who are not at the end of life, and to further explore the effects of opioids on immune system function and quality of life in these individuals.

When Physical and Social Pain Coexist: Insights Into Opioid Therapy.

The US opioid epidemic challenges us to rethink our understanding of the function of opioids and the nature of chronic pain. We have neatly separated opioid use and abuse as well as physical and social pain in ways that may not be consistent with the most recent neuroscientific and epidemiological research. Physical injury and social rejection activate similar brain centers. Many of the patients who use opioid medications long term for the treatment of chronic pain have both physical and social pain, but these medications may produce a state of persistent opioid dependence that suppresses the endogenous opioid system that is essential for human socialization and reward processing. Recognition of the social aspects of chronic pain and opioid action can improve our treatment of chronic pain and our use of opioid medications.

Complex Persistent Opioid Dependence with Long-term Opioids: a Gray Area That Needs Definition, Better Understanding, Treatment Guidance, and Policy Changes.

The multitude of treatments available for tens of millions of US adults with moderate/severe chronic pain have limited efficacy. Long-term opioid therapy (LTOT) is a widely available option for controlling pain among patients with chronic pain refractory to other treatments. The recent recognition of LTOT inefficacy and complications has led to more frequent opioid tapering, which in turn has revealed its own set of complications. The occurrence of the same set of symptoms-worsening pain, declining function, and clinical instability-in contrasting contexts of LTOT ineffectiveness and opioid tapering has led to increasing recognition of the utility of complex persistent opioid dependence (CPOD), a clinically distinct but biologically similar state compared with opioid use disorder as an explanatory diagnosis/heuristic. Recent guidelines for LTOT tapering have incorporated buprenorphine treatment based on CPOD concepts as a recommended treatment for problems due to opioid tapering with limited supportive evidence. The increasing utilization of buprenorphine for both LTOT ineffectiveness and opioid tapering problems raises the urgent need for a review of the clinical definition, mechanisms, and treatment of CPOD and pertinent policies. In this manuscript, we discuss various issues related to CPOD that requires further clarification through research and policy development.

The conundrum of opioid tapering in long-term opioid therapy for chronic pain: A commentary.

BACKGROUND: In response to the opioid epidemic and new guidelines, many patients on high-dose long term opioid therapy (LTOT) for chronic pain are getting tapered off opioids. As a result, a unique clinical challenge is emerging: while many on LTOT have poor pain control, functional decline, psychiatric instability, aberrancies and misuse, these issues may often worsen with opioid tapering. Currently, a clear explanation and practical guidance on how to manage this perplexing clinical scenario is lacking. METHODS: We offer a commentary with our perspective on possible mechanisms involved in this clinical phenomena and offer practical management guidance, supported by available evidence. RESULTS: It is not well recognized that allostatic opponent process involved in development of opioid dependence can cause worsening pain, functional status, sleep and psychiatric symptoms over time, and significant fluctuation of pain and other affective symptoms due to their bidirectional dynamic interaction with opioid dependence ('affective dynamism'). These elements of complex persistent dependence (CPD), the grey area between simple dependence and addiction, can lead to escalating and labile opioid need, often generating aberrant behaviors. Opioid tapering, a seemingly logical intervention in this situation, may lead to worsening of pain, function and psychiatric symptoms due to development of protracted abstinence syndrome. We offer practicing clinicians management principles and practical guidance focused on management of CPD in addition to chronic pain in these difficult clinical scenarios. CONCLUSION: Awareness of the science of the neuroplasticity effects of repeated use of opioids is necessary to better manage these patients with complex challenges.

Opioids for the Treatment of Chronic Pain: Mistakes Made, Lessons Learned, and Future Directions.

An overreliance on opioids has impacted all types of pain management, making it undoubtedly a root cause of the "epidemic" of prescription opioid abuse in the United States. Yet, an examination of the statistics that led the US Centers for Disease Control and Prevention to declare that prescription opioid abuse had reached epidemic levels shows that the abuse occurrences and deaths are arising outside the hospital or hospice setting, which strongly implicates the outpatient use of opioids to treat chronic pain. Such abuse and related deaths are occurring in chronic pain patients themselves and also through diversion. Overprescribing to outpatients has afforded distressed and vulnerable individuals access to these highly addictive drugs. The focus of this article is on what we have learned since opioid treatment of chronic pain was first popularized at the end of the 20th century and how this new information can guide chronic pain management in the future.

Pains Revisited.

OBJECTIVES: The management of pain patients has not evolved as rapidly as envisioned when IASP was founded almost 50 years ago. We sought to identify factors that could contribute to this situation, with a focus on concepts of pain and the education of pain physicians. METHODS: Relevant literature describing new strategies for diagnosing and managing patients with high-impact chronic pain was reviewed. RESULTS: It appears that the acute-chronic dichotomy has outlived its usefulness and pains should be identified as of peripheral origin or due to central processing errors. Pains of peripheral origin and those of central processing errors require different diagnostic and therapeutic strategies. DISCUSSION: Peripheral treatments and opioids are not effective for central pains. When the cause of the pain lies in the central nervous system, a more centrally focused approach is needed to minimize wasteful pursuit of peripheral causes. The education and training of pain physicians should reflect the skills needed to address these 2 very different clinical problems.

Core competencies for pain management: results of an interprofessional consensus summit.

OBJECTIVE: The objective of this project was to develop core competencies in pain assessment and management for prelicensure health professional education. Such core pain competencies common to all prelicensure health professionals have not been previously reported. METHODS: An interprofessional executive committee led a consensus-building process to develop the core competencies. An in-depth literature review was conducted followed by engagement of an interprofessional Competency Advisory Committee to critique competencies through an iterative process. A 2-day summit was held so that consensus could be reached. RESULTS: The consensus-derived competencies were categorized within four domains: multidimensional nature of pain, pain assessment and measurement, management of pain, and context of pain management. These domains address the fundamental concepts and complexity of pain; how pain is observed and assessed; collaborative approaches to treatment options; and application of competencies across the life span in the context of various settings, populations, and care team models. A set of values and guiding principles are embedded within each domain. CONCLUSIONS: These competencies can serve as a foundation for developing, defining, and revising curricula and as a resource for the creation of learning activities across health professions designed to advance care that effectively responds to pain.

Questioning the Right to Pain Relief and Its Role in the Opioid Epidemic.

The new discipline of palliative care helped to establish the right to pain relief at the end of life and the necessity of using opioids to achieve that goal. Professional pain organizations followed the United Nations' model for universal human rights in their declaration of a universal right to pain management. Both palliative care and pain medicine specialties worked to establish pain as a legitimate focus of medical treatment separate from its association with disease. Pain intensity became the metric used to determine the need for treatment and the success of that treatment. Opioids were favored as the most reliable and feasible means to reduced pain intensity. The Harrison Act of 1914 restricted legitimate opioid use to that prescribed by medical professionals as analgesics. This legislation helped establish opioids as specific painkillers that had a distinct capacity to induce addiction. This understanding of opioids as having distinct and separable analgesic and addictive potential was challenged by the 1970s discovery of an endogenous opioid system, which integrates pain and reward functions to support survival. Our modern pain neurophysiology places the patient with pain in a passive position from which it makes sense to assert a right to pain relief. To prevent future opioid epidemics we need to abandon clinical outpatient use of pain intensity scores and redefine the medical necessity of pain treatment as less about the reduction of pain intensity and more about the capacity to pursue personally valued activities.

Reconsidering Fordyce's classic article, "Pain and suffering: what is the unit?" to help make our model of chronic pain truly biopsychosocial.

ABSTRACT: The biopsychosocial model (BPS) of chronic pain aspires to be comprehensive, incorporating psychological and social factors omitted from biomedical models. Although psychosocial factors are viewed as highly influential in understanding behavioral and psychological responses to pain, these factors are usually viewed as modifiers of biological causes of the experience of pain itself, rather than as equal contributors to pain. To further advance the BPS model, we re-examine a classic 1994 article by Wilbert "Bill" Fordyce, "Pain and suffering: what is the unit?" In this article, Fordyce suggested that pain-related disability and suffering should be viewed as "transdermal," as having causes both inside and outside the body. We consider Fordyce's article theoretically important because this concept allows us to more fully break free of the medical model of chronic pain than customary formulations of the BPS model. It makes it possible to place psychological and social factors on an equal footing with biological ones in explaining pain itself and to remove distinctions between pain mechanisms and pain meanings. The brain's salience network now offers a platform on which diverse influences on pain experience-from nociception to multisensory indicators of safety or danger-can be integrated, bridging the gap between impersonal nociceptive mechanisms and personal meanings. We also argue that Fordyce's article is practically important because this concept expands the BPS model beyond the bounds of the clinical encounter, opening the door to the full range of social, psychological, and biological interventions, empowering patients and nonmedical providers to tackle chronic pain.

Epidural pain relief versus systemic opioid-based pain relief for abdominal aortic surgery.

BACKGROUND: Epidural analgesia offers greater pain relief compared to systemic opioid-based medications, but its effect on morbidity and mortality is unclear. This review was originally published in 2006 and was updated in 2011. OBJECTIVES: To assess the benefits and harms of postoperative epidural analgesia in comparison with postoperative systemic opioid-based pain relief for adult patients who underwent elective abdominal aortic surgery. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 11) via Ovid; Ovid MEDLINE (from inception to week 1 November 2010); and EMBASE (from inception to week 1, November 2010). The original search was performed in 2004. We assessed non-English language reports and contacted researchers in the field. We did not seek unpublished data. SELECTION CRITERIA: We included all randomized and quasi-randomized controlled trials comparing postoperative epidural analgesia and postoperative systemic opioid-based analgesia for adult patients who underwent elective open abdominal aortic surgery. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information and data. MAIN RESULTS: We included 15 trials that involved 1297 patients (633 patients received epidural analgesia and 664 received systemic opioid analgesia) in this review. This included one trial we found in our updated search and one trial from our original review that had been awaiting translation. The epidural analgesia group showed significantly lower visual analogue scale scores for pain on movement (up to postoperative day three) regardless of the site of the epidural catheter and epidural formulation. The postoperative duration of tracheal intubation and mechanical ventilation was significantly shorter, by about 48%, in the epidural analgesia group. The overall event rates of myocardial infarction, acute respiratory failure (defined as an extended need for mechanical ventilation), gastrointestinal complications, and renal complications were significantly lower in the epidural analgesia group. AUTHORS' CONCLUSIONS: Epidural analgesia provides better pain relief (especially during movement) in the period up to three postoperative days. It reduces the duration of postoperative tracheal intubation by roughly half. The occurrence of prolonged postoperative mechanical ventilation, myocardial infarction, gastric complications and renal complications was reduced by epidural analgesia. However, current evidence does not confirm the beneficial effect of epidural analgesia on postoperative mortality and other types of complications.

Is Chronic Pain a Disease?

It was not until the twentieth century that pain was considered a disease. Before that it was managed medically as a symptom. The motivations for declaring chronic pain a disease, whether of the body or of the brain, include increasing its legitimacy as clinical problem and research focus worthy of attention from healthcare and research organizations alike. But 1 problem with disease concepts is that having a disease favors medical solutions and tends to reduce patient participation. We argue that chronic pain, particularly chronic primary pain (recently designated a first tier pain diagnosis in International Diagnostic Codes 11), is a learned state that is not intransigent even if it has biological correlates. Chronic pain is sometimes a symptom, and may sometimes be its own disease. But here we question the value of a disease focus for much of chronic pain for which patient involvement is essential, and which may need a much broader societal approach than is suggested by the disease designation. PERSPECTIVE: This article examines whether designating chronic pain a disease of the body or brain is helpful or harmful to patients. Can the disease designation help advance treatment, and is it needed to achieve future therapeutic breakthrough? Or does it make patients over-reliant on medical intervention and reduce their engagement in the process of recovery?

Long-term prescription opioid users' risk for new-onset depression increases with frequency of use.

ABSTRACT: Long-term opioid therapy (LTOT) is associated with increased risk for depression. It is not known if the frequency of opioid use during LTOT is associated with new-onset depression. We used Optum's de-identified Integrated Claims-Clinical dataset (2010-2018) to create a cohort of 5146 patients, 18 to 80 years of age, with an encounter or claims in the year before new LTOT. New LTOT was defined by >90-day opioid use after remaining opioid free for 6 months. Opioid use frequency during the first 90 days of LTOT was categorized into occasional use (<50% days covered), intermittent use (50% to <80% days covered), frequent use (80% to <90% days covered), and daily use (≥90% days covered). Propensity scores and inverse probability of exposure weighting controlled for confounding in models estimating risk for new-onset depression. Patients were on average 54.5 (SD ± 13.6) years of age, 55.7% were female, 72.5% were White, and 9.5% were African American. After controlling for confounding, daily users (hazard ratio = 1.40; 95% confidence interval: 1.14-1.73) and frequent users (hazard ratio = 1.34; 95% confidence interval: 1.05-1.71) were significantly more likely to develop new-onset depression compared with occasional users. This association remained after accounting for the contribution of post-index pain diagnoses and opioid use disorder. In LTOT, risk for new depression episodes is up to 40% greater in near-daily users compared with occasional users. Patients could reduce depression risk by avoiding opioid use on as many low pain days as possible. Repeated screening for depression during LTOT is warranted.

The Right to Pain Relief: Its Origins in End-of-life Care and Extension to Chronic Pain Care.

OBJECTIVES: The claim of a right to pain relief was made in recent decades by pain professionals, courts, and patient advocacy groups and likely contributed to increased opioid prescribing, overdose deaths, and addictions, but the origins and nature of this right have not been investigated. MATERIALS AND METHODS: Relevant clinical, ethical, and legal literature concerning patient rights to pain care was reviewed. RESULTS: The record describes the effort to improve end-of-life and cancer pain care in the 1980s and 1990s, which simultaneously legitimated pain relief as an independent goal of medical care and opioids as a safe and effective means to achieve this relief. In 1997, the US Supreme Court denied the right to assisted suicide but affirmed a right to palliative care to prevent dying in overwhelming pain. Other guidelines and regulations extended this right to pain relief from end-of-life care to chronic pain care, along with the titrate-to-effect principle, which specified that the correct opioid dose was the dose that relieved pain. DISCUSSION: The most important consequence of combining the right to pain relief with the titrate-to-effect principle was the idea that a high pain score must not be ignored. This extension of the right to pain relief neglected important differences between end-of-life care and chronic pain care including: time frame, clinical setting and context, target of titration, and nature of iatrogenic harms. To help end our current opioid epidemic and prevent a future epidemic, we need to demedicalize pain and reintegrate it with the rest of human suffering as an experience connected to other personal behaviors and meanings.

Opioid dosing among patients with 3 or more years of continuous prescription opioid use before and after the CDC opioid prescribing guideline.

BACKGROUND: Opioid doses declined after the Centers for Disease Control (CDC) opioid prescribing guideline was published. However, it is unknown if dose declines occurred in patients with ≥ 3 years of continuous opioid use. METHODS: Optum® de-identified integrated Electronic Health Record and claims data were used to create an adult sample (n = 400) with continuous opioid use for 18 months before and after the guideline publication. Based on the morphine milligram equivalent (MME) distribution at Month 1, patients were categorized into 1-50, 51-100, 101-200, and >200 mg baseline MME. Interrupted time series analysis using segmented mixed linear regression models stratified on baseline MME estimated average monthly changes in MME in the 18-months pre- and post-guideline, before and after adjusting for time-varying pain conditions, psychiatric disorders and benzodiazepine prescription. RESULTS: Patients were 59.6 (SD±11.8) years of age, 55.8% female and 84.0% white race. For 1-50 MME, monthly dose slope was significantly (p<0.0001) flatter post-guideline (pre b = 0.34 MME/month vs. post b = 0.12 MME/month). For 51-100 MME, the pre- and post-guideline dose slopes did not significantly differ (pre b = 0.60 MME/month vs. post b = 0.27 MME/month). For 101-200 MME, post-guideline dose slope was significantly (p<0.0001) steeper and decreasing post-guideline (pre b = 0.11 MME/month vs. post b= -1.33 MME/month). Among >200 MME, dose decreased in the pre- and post-guideline periods, and post-guideline decline was significantly (p<0.0001) steeper (b= -1. 86 MME/month vs. b= -4.13 MME/month). CONCLUSIONS: Among patients on multiyear opioid therapy, the CDC guideline was associated with a modest change in dosing, except for patients on very high doses. The guideline was not associated with decreasing MME among lower-dose, long-term users.

Depression and Buprenorphine Treatment in Patients with Non-cancer Pain and Prescription Opioid Dependence without Comorbid Substance Use Disorders.

BACKGROUND: Depression occurs in 40% of patients with prescription opioid dependence (POD). Existing studies of the association between depression and buprenorphine (BUP) treatment for POD are inconsistent and often include patients with comorbid substance use disorders (SUD). We estimated the association between depression and BUP use in patients with pain and POD and free of comorbid SUD. METHODS: Optum® de-identified Electronic Health Record dataset from 2010 to 2018 was used to identify 5,529 patients with chronic pain, with and without depression, receiving prescription opioids and free of substance use disorder diagnoses for one year before POD diagnoses. Unadjusted and adjusted Cox proportional hazard models and negative binomial regression models were computed to estimate the association between depression and time to BUP start, number of BUP prescriptions in the year after BUP start and time to >30 day BUP gap. RESULTS: Patients' mean age was 52.4 (SD±15.3) years, 62% were female and 84% were white and 4.9% (n=270) started BUP. Depression was not associated with BUP initiation.. Among BUP starters, depression vs. no depression, was significantly associated with receiving 29% fewer BUP prescriptions (RR=0.71; 95%CI: 0.51-0.98) and an increased risk for > 30 day gap (HR=1.76; 95%CI:1.01-3.09). LIMITATIONS: Missing data prevented measuring BUP dose. CONCLUSIONS: Depression is likely associated with earlier BUP treatment dropout. Depression related medication non-adherence or possible worsening of depression following BUP taper could explain results. Research is needed to determine if depression severity is associated with BUP dose trajectories and multi-year BUP retention..