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Howard S Smith,1,† John F Peppin2,3 1Department of Anesthesiology, Albany Medical College, Albany, NY, USA; 2Global Scientific Affairs, Mallinckrodt Pharmaceuticals, St Louis, MO, USA; 3Center for Bioethics, Pain Management and Medicine, St Louis, MO, USA†Author deceased May 18, 2013 Abstract: Patients requiring chronic opioid therapy may not respond to or tolerate the first opioid prescribed to them, necessitating rotation to another opioid. They may also require dose increases for a number of reasons, including worsening disease and increased pain. Dose escalation to restore analgesia using the primary opioid may lead to increased adverse events. In these patients, rotation to a different opioid at a lower-than-equivalent dose may be sufficient to maintain adequate tolerability and analgesia. In published trials and case series, opioid rotation is performed either using a predetermined substitute opioid with fixed conversion methods, or in a manner that appears to be no more systematic than trial and error. In clinical practice, opioid rotation must be performed with consideration of individual patient characteristics, comorbidities (eg, concurrent psychiatric, pulmonary, renal, or hepatic illness), and concurrent medications, using flexible dosing protocols that take into account incomplete opioid cross-tolerance. References cited in this review were identified via a search of PubMed covering all English language publications up to May 21, 2013 pertaining to opioid rotation, excluding narrative reviews, letters, and expert opinion. The search yielded a total of 129 articles, 92 of which were judged to provide relevant information and subsequently included in this review. Through a review of this literature and from the authors' empiric experience, this review provides practical information on performing opioid rotation in clinical practice. Keywords: chronic pain, opioid rotation, opioid analgesics

Howard S SmithDepartments of Anesthesiology, Medicine, and Physical Medicine and Rehabilitation Albany Medical College, Albany, NY, USAAbstract: Breakthrough pain (BTP) is a transitory pain that occurs despite the use of long-term, around-the-clock analgesia. It is highly prevalent in certain populations and places a significant burden on patients, their families, caregivers, and health-care systems. Despite its prevalence and impact, BTP is sometimes unrecognized and often undertreated. Various formulations of fentanyl – a rapid-onset opioid with short duration of action – are available for the management of BTP. The efficacy of formulations using transmucosal, transbuccal, sublingual, and intranasal administration routes has been demonstrated for BTP treatment in clinical trials. However, a lack of head-to-head trials evaluating their relative efficacy makes it challenging for physicians to reach informed decisions on the most efficacious intervention for individual patients. In the absence of clear data on the relative efficacy of fentanyl formulations, prescribing decisions need to be based on physician understanding and experience and product cost and availability, taking into account the individual patient's needs, the ability of the patient or caregivers to administer medication, and the patient's wishes. This review evaluates current pharmacologic methods of alleviating BTP and discusses factors that should be considered when selecting the most appropriate formulation for individual patients. With the range of fentanyl formulations available, it is now possible to successfully address BTP in the majority of patients.Keywords: rapid-onset opioid, breakthrough pain, pain, fentanyl

Howard S Smith,1 Eric J Smith,2 Benjamin R Smith21Department of Anesthesiology, Albany Medical College, Albany, NY; 2The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, USAAbstract: Chronic musculoskeletal pain is among the most frequent painful complaints that healthcare providers address. The bulk of these complaints are chronic low back pain and chronic osteoarthritis. Osteoarthritis is the most common form of arthritis in the United States. It is a chronic degenerative disorder characterized by a loss of cartilage, and occurs most often in older persons. The management of osteoarthritis and chronic low back pain may involve both nonpharmacologic (eg, weight loss, resistive and aerobic exercise, patient education, cognitive behavioral therapy) and pharmacologic approaches. Older adults with severe osteoarthritis pain are more likely to take analgesics than those with less severe pain. The pharmacologic approaches to painful osteoarthritis remain controversial, but may include topical as well as oral nonsteroidal antiinflammatory drugs, acetaminophen, duloxetine, and opioids. The role of duloxetine for musculoskeletal conditions is still evolving.Keywords: pain, musculoskeletal, duloxetine, osteoarthritis, low back, serotonin-norepinephrine reuptake inhibitor

Clinicians understand that individual patients differ in their response to specific opioid analgesics and that patients may require trials of several opioids before finding an agent that provides effective analgesia with acceptable tolerability. Reasons for this variability include factors that are not clearly understood, such as allelic variants that dictate the complement of opioid receptors and subtle differences in the receptor-binding profiles of opioids. However, altered opioid metabolism may also influence response in terms of efficacy and tolerability, and several factors contributing to this metabolic variability have been identified. For example, the risk of drug interactions with an opioid is determined largely by which enzyme systems metabolize the opioid. The rate and pathways of opioid metabolism may also be influenced by genetic factors, race, and medical conditions (most notably liver or kidney disease). This review describes the basics of opioid metabolism as well as the factors influencing it and provides recommendations for addressing metabolic issues that may compromise effective pain management. Articles cited in this review were identified via a search of MEDLINE, EMBASE, and PubMed. Articles selected for inclusion discussed general physiologic aspects of opioid metabolism, metabolic characteristics of specific opioids, patient-specific factors influencing drug metabolism, drug interactions, and adverse events. [ABSTRACT FROM AUTHOR]

It appears that in COX-2 selective inhibitors may increase the risk of major adverse cardiovascular events. Various potential mechanisms are presented whereby COX-2 selective inhibitors may enhance the risk of cardiovascular events in certain patients. It is conceivable that different mechanisms may be involved in different circumstances and that multifactorial mechanisms may occasionally be operating in conjunction with one another. [ABSTRACT FROM AUTHOR]

It is proposed that under certain circumstances peripheral nerve may exist in a poorly or nonfunctional reversible state [termed hibernating peripheral nerve (HPN)] after neural insult. Furthermore, it is speculated that certain high intraneural concentrations of lidocaine may conceivably facilitate a hypothetical state of hibernating peripheral nerve. [ABSTRACT FROM AUTHOR]

Piriformis syndrome tends to be overlooked as an etiology of low back pain/buttock pain in the palliative care population. Increased familiarity with this diagnosis and its treatment may increase its recognition and facilitate optimal treatment. Optimal treatment approaches to the clinical problem of piriformis syndrome may provide improved analgesia and function while minimizing adverse effects. [ABSTRACT FROM AUTHOR]

Painful diabetic polyneuropathy (DPN) remains a significant persistent pain problem which detracts significantly from the quality of life of many patients. Multiple analgesics including antidepressants, antiepileptic drugs, opioids, topical local anesthetics, tramadol preparations, as well as other enteral, parenteral, and topical analgesics have been utilized to treat painful diabetic polyneuropathy with varying degrees of success. Insulin has been administered to some patients with painful DPN in efforts to achieve 'tight glycemic control'--hoping to minimize the morbidity and mortality of various diabetic complications as well as improve symptoms of painful DPN. This article proposes that the administration of insulin and/or C-peptide and its signaling may contribute to relief from painful DPN-not wholly due to effects on glucose but in part due to their specific 'inherent' effects on other processes including: oxidative stress, inflammation, apoptosis, and PARP function. [ABSTRACT FROM AUTHOR]

The class of medications known as beta blockers, which antagonize the beta adrenergic receptor, are used extensively in cardiovascular medicine. It is conceivable that in certain painful circumstances, beta blockers modulate nociceptive processes and thus may be useful on occasion as analgesic adjuvant medications. [ABSTRACT FROM AUTHOR]

Neuropathic pain remains a difficult clinical treatment dilemma. Despite numerous therapeutic approaches which have been developed, many patients continue to suffer. One difficulty which may lead to suboptimal neuropathic pain treatment outcomes is that of not being able to match particular therapeutic approaches to important nociceptive specific mechanisms/processes involved in a particular patient with pain. It is theorized that the phenomenon of apoptosis and/or its associated signaling pathways-may at least partly contribute to hyperalgesia and/or pain states in certain circumstances. The term algoptosis is coined to refer to phenomena in which neuronal (and/or glial) apoptosis and its associated cellular/molecular mechanisms and signaling pathways-contribute to the modulation of nociceptive processes (i.e., processes leading to potential cell death. It is conceivable that certain pain states may exist in which apoptosis contributes to nociception-thus, it would be conceivable that treatment strategies designed to limit and/or reverse apoptotic processes-may possess analgesic and/or antihyperalgesic qualities. [ABSTRACT FROM AUTHOR]

Overall the treatment of persistent neuropathic pain remains suboptimal. In part, this may be related to an incomplete appreciation of the mechanisms involved in contributing to neuropathic pain in individual patients. A novel theory is presented which is proposed to potentially explain a peripheral component of nociception which may be involved in a subset of patients with persistent neuropathic pain. [ABSTRACT FROM AUTHOR]

The precise biochemical mechanisms which lead to painful diabetic polyneuropathy are complex, multifactorial, and remain elusive. Early changes in nerve function may pre-date elevated serum glucose levels by years. It is conceivable that disturbances in the insulinlike growth factor system as well as the levels of insulin and/or C-peptide may play a role in contributing to pain and/or neural dysfunction in patients suffering from painful diabetic polyneuropathy. [ABSTRACT FROM AUTHOR]

Pain is usually elicited by the activation of specific visceral or non-visceral (somatic) nociceptors ('nociceptive pain'). However, it may also result from injury to or dysfunction of peripheral sensory nerve fibers or from damage to or dysfunction of the central nervous system itself ('neuropathic pain'). Although acute nociceptive pain fulfills a warning role regarding possible systemic injury, chronic and/or neuropathic pain may be maladaptive. Cancer-related neuropathic pain generally results from compression irritation, or infiltration of nerves by the tumor, nerve trauma from operative procedures, or neuropathic pain related to the treatment of cancer itself. Management of neuropathic pain may include the use of opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), antidepressants, anticonvulsants, local anesthetics, and other adjuvant medications. Intractable neuropathic pain may require the use of intraspinal delivery of medication or anesthetic and neurosurgical procedures. The purpose of this article is to provide a global account of the mechanisms involved in the development of neuropathic pain. Particular attention is focused on cellular aspects and on the consequences of peripheral nervous system (PNS) injury. Further, therapies used for the management of cancer related neuropathic pain are reviewed; new therapeutic approaches based on recent findings from basic research are discussed. An improved understanding of the origins of neuropathic pain should facilitate the development of novel strategies for effective treatment of cancer-related neuropathic pain. [ABSTRACT FROM AUTHOR]

Many of the analgesics which are utilized in efforts to diminish pain, act on G-protein, coupled receptors (GPCRs) to initiate/activate a number of second messenger effects and signaling pathways. It is conceivable that the direct or indirect manipulation/modulation of small GT Pases and other associated enzymes/proteins which act downstream from GPCRs may be useful as analgesic adjuncts which may lead to increased efficacy or decreased adverse effects. [ABSTRACT FROM AUTHOR]

This paper discusses the treatment of pain in the palliative care patient, specifically the use of meloxicam and recent advances in agents with cyclooxygenase-2 (COX-2) selectivity. Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) that preferentially inhibits COX-2 more than cyclooxygenase-1 (COX-1), especially at low doses, thereby offering advantages over traditional nonselective NSAIDs. New COX-2 selective agents are discussed, including valdecoxib, parecoxib, etoricoxib, and COX-189. [ABSTRACT FROM AUTHOR]

Various forms of distant healing (DH), including prayer and 'psychic healing,' are widely practiced, but insufficient formal research has been done to indicate whether such efforts actually affect health. We report on a double-blind randomized trial of DH in 40 patients with advanced AIDS. Subjects were pair-matched for age, CD4+ count, and number of AIDS-defining illnesses and randomly selected to either 10 weeks of DH treatment or a control group. DH treatment was performed by self-identified healers representing many different healing and spiritual traditions. Healers were located throughout the United States during the study, and subjects and healers never met. Subjects were assessed by psychometric testing and blood draw at enrollment and followed for 6 months. At 6 months, a blind medical chart review found that treatment subjects acquired significantly fewer new AIDS-defining illnesses (0.1 versus 0.6 per patient, P=0.04), had lower illness severity (severity score 0.8 versus 2.65, P=0.01), fewer hospitalizations (0.15 versus 0.6, P=0.04), and fewer days of hospitalization (0.5 versus 3.04, P=0.04). Treated subjects also showed significantly improved mood compared with controls (Profile of Mood States score -26 versus 14, P=0.02). There were no significant differences in CD4+ counts. These data support the possibility of a DH in AIDS and suggest the value of further research. [ABSTRACT FROM AUTHOR]