Joseph V. Pergolizzi

Opioids and the Management of Chronic Severe Pain in the Elderly: Consensus Statement of an International Expert Panel with Focus on the Six Clinically Most Often Used World Health Organization step III Opioids (Buprenorphine, Fentanyl, Hydromorphone, Methadone, Morphine, Oxycodone)

1. The use of opioids in cancer pain:  The criteria for selecting analgesics for pain treatment in the elderly include, but are not limited to, overall efficacy, overall side‐effect profile, onset of action, drug interactions, abuse potential, and practical issues, such as cost and availability of the drug, as well as the severity and type of pain (nociceptive, acute/chronic, etc.). At any given time, the order of choice in the decision‐making process can change.

Current Knowledge of Buprenorphine and Its Unique Pharmacological Profile

Despite the increasing clinical use of transdermal buprenorphine, questions have persisted about the possibility of a ceiling effect for analgesia, its combination with other μ‐opioid agonists, and the reversibility of side effects. In October 2008, a consensus group of experts met to review recent research into the pharmacology and clinical use of buprenorphine. The objective was to achieve consensus on the conclusions to be drawn from this work. It was agreed that buprenorphine clearly behaves as a full μ‐opioid agonist for analgesia in clinical practice, with no ceiling effect, but that there is a ceiling effect for respiratory depression, reducing the likelihood of this potentially fatal adverse event. This is entirely consistent with receptor theory. In addition, the effects of buprenorphine can be completely reversed by naloxone. No problems are encountered when switching to and from buprenorphine and other opioids, or in combining them. Buprenorphine exhibits a pronounced antihyperalgesic effect that might indicate potential advantages in the treatment of neuropathic pain. Other beneficial properties are the compounds favorable safety profile, particularly in elderly patients and those with renal impairment, and its lack of effect on sex hormones and the immune system. The expert group agreed that these properties, as well as proven efficacy in severe pain and favorable tolerability, mean that buprenorphine can be considered a safe and effective option for treating chronic cancer and noncancer pain.

Pharmacological treatment of chronic pain – the need for CHANGE

Abstract Background: Although chronic pain affects around 20% of adults in Europe and the USA, there is substantial evidence that it is inadequately treated. In June 2009, an international group of pain specialists met in Brussels to identify the reasons for this and to achieve consensus on strategies for improving pain management. Scope: Literature on chronic pain management was reviewed, and information presented to and discussed by a panel of experts. Findings: It was agreed that guidelines are not universally accepted by those involved in pain management, and pain treatment seems to be driven mainly by tradition and personal experience. Other factors include poor communication between patients and physicians, the side effects of analgesic drugs, and limited individualisation of therapy. Difficulty in maintaining the balance between adequate pain relief and acceptable tolerability, particularly with strong opioids, can lead to the establishment of a ‘vicious circle’ that alternates between lack of efficacy and unpleasant side effects, prompting discontinuation of treatment. The medical community’s understanding of the physiological differences between nociceptive pain and neuropathic pain, which is often more severe and difficult to treat, could be improved. Increasing physicians’ knowledge of the pharmacological options available to manage these different pain mechanisms offers the promise of better treatment decisions and more widespread adoption of a multi-mechanistic approach; this could involve loosely combining two substances from different drug classes, or administering an analgesic with two different mechanisms of action. In some circumstances, a single compound capable of addressing both nociceptive and neuropathic pain is desirable. Conclusions: To improve patient outcomes, a thorough understanding of pain mechanisms, sensitisation and multi-mechanistic management is required. Universal, user-friendly educational tools are therefore required to familiarise physicians with these topics, and also to improve communication between physicians and their pain patients, so that realistic expectations of treatment can be established.

The impact of pain on labor force participation, absenteeism and presenteeism in the European Union

Abstract Objectives: The aims of this paper are to generate estimates of the association between the experience and burden of pain, by severity and frequency, with (1) labor force participation and workforce status in five EU countries (the UK, France, Spain, Germany and Italy) and (2) patterns of absenteeism and presenteeism for the employed workforce. Methods: Data are from the internet-based 2008 National Health and Wellness Survey (NHWS). This survey covers both those who report experiencing pain in the last month as well as the no pain population. A series of regression models are developed with the no pain group as the reference category. The impact of pain, categorized by severity and frequency reported, is assessed within a labor supply framework for (1) labor force participation and (2) absenteeism and presenteeism. In the former case both binomial and multinomial logistic models are estimated; in the latter case ordered logit models are estimated. Results: The results demonstrate that, in the context of health status, the experience of frequent severe and moderate pain has a dominant, independent and negative association with labor force participation and employment status as well as absenteeism and presenteeism. The presence of severe daily pain is associated with a 20-point reduction in the probability of being employed full-time; with moderate daily pain associated with a 10-point reduction. The impact of pain is far greater than the potential impact of other health status measures (e.g., chronic comorbidities and BMI). The experience of pain, notably severe and frequent pain, also outstrips the impact of other health status factors in absenteeism and presenteeism. Conclusions: The experience of pain, in particular severe daily pain, has a substantial negative association with labor force participation in these five European countries as well as reported absenteeism and presenteeism. As a measure of health status, it clearly outweighs other health status measures. Whether or not pain is considered as a disease in its own right, the experience of chronic pain, as defined here, presents policy makers with a major challenge. Programs to relieve the burden of pain in the community clearly have the potential for substantial benefits from societal, individual and employer perspectives.

Intravenous acetaminophen reduces postoperative nausea and vomiting: A systematic review and meta-analysis

Summary Prophylactically administered intravenous acetaminophen for postsurgical pain reduces postoperative nausea and vomiting. This effect is unrelated to the opioid‐sparing effect, but correlates with superior pain control. Abstract Opioids are a key risk factor for postoperative nausea and vomiting (PONV). As intravenous (i.v.) acetaminophen reduces postoperative pain and opioid requirements, one would expect i.v. acetaminophen to be associated with a lower incidence of opioid‐induced side effects, including PONV. We conducted a systematic search using Medline and Cochrane databases supplemented with hand search of abstract proceedings to identify randomized‐controlled trials of i.v. acetaminophen. Inclusion criteria were (a) randomized for i.v. acetaminophen vs a placebo control, (b) general anesthesia, and (c) reported or obtainable PONV outcomes. Primary outcome was postoperative nausea and secondary outcome was postoperative vomiting. We included 30 studies with 2364 patients (1223 in the acetaminophen group, 1141 in the placebo group). The relative risk (95% confidence interval) was 0.73 (0.60–0.88) for nausea and 0.63 (0.45–0.88) for vomiting. Data showed significant heterogeneity for both nausea (P = 0.02, I2 = 38%) and vomiting (P = 0.006, I2 = 47%), but were homogeneous when studies were grouped according to timing of first administration: i.v. acetaminophen reduced nausea when given prophylactically either before surgery, 0.54 (0.40–0.74), or before arrival in the postanesthesia care unit, 0.67 (0.55–0.83); but not when given after the onset of pain, 1.12 (0.85–1.48). When i.v. acetaminophen was given prophylactically, the reduction of nausea correlated with the reduction of pain (odds ratio 0.66, 0.47–0.93), but not with reduction in postoperative opioids (odds ratio 0.89, 0.64–1.22). Prophylactically administered i.v. acetaminophen reduced PONV, mainly mediated through superior pain control.

The societal impact of pain in the European Union: health-related quality of life and healthcare resource utilization

Abstract Objectives: This paper reports on the results of a series of quantitative assessments of the association of severe and frequent pain with health-related quality of life and healthcare resource utilization in five European countries. Methods: The analysis contrasts the contribution of the increasing severity and frequency of pain reported against respondents reporting no pain in the previous month. The data are taken from the 2008 National Health and Wellness Survey. Single-equation generalized linear regression models are used to evaluate the association of pain with the physical and mental component scores of the SF-12 questionnaire as well as health utilities generated from the SF-6D. In addition, the role of pain is assessed in its association with healthcare provider visits, emergency room visits and hospitalizations. Results: The results indicate that the experience of pain, notably severe and frequent pain, is substantial and is significantly associated with the SF-12 physical component scores, health utilities and all aspects of healthcare resource utilization, which far outweighs the role of demographic and socioeconomic variables, health risk factors (in particular body mass index) and the presence of comorbidities. In the case of severe daily pain, the marginal contribution of the SF-12 physical component score is a deficit of −17.86 compared to those reporting no pain (population average score 46.49), while persons who are morbidly obese report a deficit of only −6.63 compared to those who are normal weight. The corresponding association with health utilities is equally dramatic with a severe daily pain deficit of −0.19 compared to those reporting no pain (average population utility 0.71). Conclusions: For the five largest EU countries, the societal burden of pain is considerable. The experience of pain far outweighs the contribution of more traditional explanations of HRQoL deficits as well as being the primary factor associated with increased provider visits, emergency room visits and hospitalizations.

Tapentadol in the management of chronic low back pain: A novel approach to a complex condition?

Chronic pain affects approximately 1 in 5 people in Europe, and around half of sufferers receive inadequate pain management. The most common location is the lower back. Pharmacological treatment of this condition is challenging because of the range of causative mechanisms and the difficulty of balancing analgesic efficacy and tolerability. An international panel of clinical pain specialists met in September, 2009, to discuss the treatment of chronic low back pain, and to review preclinical and clinical data relating to the new analgesic, tapentadol. A lack of consensus exists on the best treatment for low back pain. The range of regularly prescribed pharmacological agents extends from nonopioids (paracetamol, NSAIDs, and COX-2 inhibitors) to opioids, antidepressants and anticonvulsants. Pain relief may be compromised, however, by an undetected neuropathic component or intolerable side effects. Treatment is potentially life-long and effective analgesics are urgently needed, with demonstrable long-term safety. Combining separate agents with different mechanisms of action could overcome the limitations of present pharmacological therapy, but clinical evidence for this approach is currently lacking. Tapentadol combines μ-opioid agonism with noradrenaline reuptake inhibition in a single molecule. There is strong evidence of synergistic antinociception between these two mechanisms of action. In preclinical and clinical testing, tapentadol has shown efficacy against both nociceptive and neuropathic pain. Preclinical data indicate that tapentadol’s μ-opioid agonism makes a greater contribution to analgesia in acute pain, while noradrenaline reuptake inhibition makes a greater contribution in chronic neuropathic pain models. Tapentadol also produces fewer adverse events than oxycodone at equianalgesic doses, and thus may have a ‘μ-sparing effect’. Current evidence indicates that tapentadol’s efficacy/tolerability ratio may be better than those of classical opioids. However, further research is needed to establish its role in pain management.

Efficacy and Tolerability of Subcutaneous Methylnaltrexone in Patients with Advanced Illness and Opioid-Induced Constipation: A Responder Analysis of 2 Randomized, Placebo-Controlled Trials.

Subcutaneous methylnaltrexone is efficacious and well tolerated in inducing bowel movements in patients with advanced illness and opioid‐induced constipation (OIC); factors determining optimal responsiveness to OIC treatment, however, have not been elucidated. This post hoc responder analysis examined the influence of demographic and baseline characteristics on methylnaltrexone efficacy and tolerability in this population.

Treatment Considerations for Cancer Pain: A Global Perspective.

Cancer pain is prevalent, undertreated, and feared by patients with cancer. In April 2013, a panel of pain experts convened in Singapore to address the treatment of cancer pain. They discussed the various types of cancer pain, including breakthrough pain, which is sometimes clinically confused with analgesic gaps. Reasons for undertreating cancer pain include attitudes of patients, clinicians, and factors associated with healthcare systems. The consequences of not treating cancer pain may include reduced quality of life for patients with cancer (who now live longer than ever), functional decline, and increased psychological stress. Early analgesic intervention for cancer pain may reduce the risk of central sensitization and chronification of pain. To manage pain in oncology patients, clinicians should assess pain during regular follow‐up visits using validated pain measurement tools and follow prescribing guidelines, if necessary referring patients with cancer to pain specialists. Many patients with cancer require opioids for pain relief. Pain associated with cancer may also relate to cancer treatments, such as chemotherapy‐induced peripheral neuropathy. Many patients with cancer are what might be considered “special populations,” in that they may be elderly, frail, comorbid, or have end‐stage organ failure. Specific pain therapy guidelines for those populations are reviewed. Patients with cancer with a history of or active substance abuse disorder deserve pain control but may require close medical supervision. While much “treatment inertia” exists in cancer pain control, cancer pain can be safely and effectively managed and should be carried out to alleviate suffering and improve outcomes.

The unique role of transdermal buprenorphine in the global chronic pain epidemic

Pain is a global epidemic, exacerbated by barriers to access of opioid analgesics. Regulations about opioids attempt to protect public health from the risks of harmful use of opioids, diversion, and dependence. Transdermal buprenorphine is an effective opioid analgesic agent with unique properties that may make it particularly well suited for more widespread use. It is a versatile analgesic product with demonstrated safety and effectiveness in cancer and noncancer pain populations. Its pharmacological properties make it a first-line opioid analgesic for geriatric patients and patients with renal dysfunction; no dosing adjustments need to be made. The 7-day transdermal delivery system is convenient for patients and promotes compliance. A low dose of buprenorphine can provide effective and well-tolerated pain relief. Although buprenorphine has been associated with certain opioid-related adverse effects, such as dizziness and nausea, it is associated with a lower rate of constipation than many other opioid analgesics. The potential for nonmedical use of buprenorphine is relatively low compared with other opioid agents. Buprenorphine has a relatively low likeability for nonmedical use and the transdermal matrix patch renders the substance particularly difficult to extract for illicit purposes.