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Supplemental Digital Content is Available in the Text., Opioids relieve acute pain, but there is little evidence to support the stability of the benefit over long-term treatment of chronic noncancer pain. Previous systematic reviews consider only group level published data which did not provide adequate detail. Our goal was to use patient-level data to explore the stability of pain, opioid dose, and either physical function or pain interference in patients treated for 12 months with abuse deterrent formulations of oxycodone and hydrocodone. All available studies in the Food and Drug Administration Document Archiving, Reporting, and Regulatory Tracking System were included. Patient-level demographics, baseline data, exposure, and outcomes were harmonized. Individual patient slopes were calculated from a linear model of pain, physical function, and pain interference to determine response over time. Opioid dose was summarized by change between baseline and the final month of observation. Patients with stable or less pain, stable or lower opioid dose, and stable or better physical function (where available) met our prespecified criteria for maintaining long-term benefit from chronic opioids. Of the complete data set of 3192 patients, 1422 (44.5%) maintained their pain level and opioid dose. In a secondary analysis of 985 patients with a measured physical function, 338 (34.3%) maintained their physical function in addition to pain and opioid dose. Of 2040 patients with pain interference measured, 788 (38.6%) met criteria in addition. In a carefully controlled environment, about one-third of patients successfully titrated on opioids to treat chronic noncancer pain demonstrated continued benefit for up to 12 months.

A systematic review of original research articles was conducted to evaluate the safety and efficacy of lidocaine infusion in the treatment of adult patients with chronic neuropathic pain.Original research from 1970 to September 2021 describing adult patients with chronic neuropathic pain receiving at least 1 dose of intravenous lidocaine was included. Extracted data included study design, sample size, patient demographics and comorbidities, etiology and duration of pain, pain intensity scores, time to pain resolution, lidocaine dose and administration frequency, lidocaine serum concentration, and adverse events. Each study was evaluated for level of evidence using the 2017 American Association of Neurology classification system.Twenty-seven studies evaluating lidocaine infusion treatment in chronic neuropathic pain met inclusion criteria. One class I study was identified for patients with neuropathic pain due to spinal cord injury . Two Class II studies were identified, one describing neuropathic pain due to peripheral nerve injury and another due to diabetic neuropathy. Across all studies, study design, participants, and experimental interventions were heterogenous with wide variation.This qualitative review found insufficient, heterogenous evidence and therefore no recommendation can be made for lidocaine infusion treatment in patients with chronic neuropathic pain due to spinal cord injury, peripheral nerve injury, diabetic neuropathy, postherpetic neuralgia, or complex regional pain syndrome type II. Larger randomized, double-blind, placebo-controlled studies are required to further establish the efficacy of lidocaine infusion in patients with these etiologies of chronic neuropathic pain.

Objective To develop consensus recommendations on urine drug monitoring (UDM) in patients with chronic pain who are prescribed opioids. Methods An interdisciplinary group of clinicians with expertise in pain, substance use disorders, and primary care conducted virtual meetings to review relevant literature and existing guidelines and share their clinical experience in UDM before reaching consensus recommendations. Results Definitive (e.g., chromatography-based) testing is recommended as most clinically appropriate for UDM because of its accuracy; however, institutional or payer policies may require initial use of presumptive testing (i.e., immunoassay). The rational choice of substances to analyze for UDM involves considerations that are specific to each patient and related to illicit drug availability. Appropriate opioid risk stratification is based on patient history (especially psychiatric conditions or history of opioid or substance use disorder), prescription drug monitoring program data, results from validated risk assessment tools, and previous UDM. Urine drug monitoring is suggested to be performed at baseline for most patients prescribed opioids for chronic pain and at least annually for those at low risk, two or more times per year for those at moderate risk, and three or more times per year for those at high risk. Additional UDM should be performed as needed on the basis of clinical judgment. Conclusions Although evidence on the efficacy of UDM in preventing opioid use disorder, overdose, and diversion is limited, UDM is recommended by the panel as part of ongoing comprehensive risk monitoring in patients prescribed opioids for chronic pain.

Constipation is a common complication of opioid therapy that contributes to substantial patient morbidity, decreased productivity, and opioid nonadherence. Other causes of constipation may occur concomitantly and should be investigated. Although evidence supporting their use is limited, the use of fiber, water, laxatives, and/or exercise is recommended in current guidelines as initial management. Peripherally acting μ-opioid receptor antagonists are important treatment options, are well-tolerated, and improve many signs and symptoms of OIC in patients taking an opioid for chronic noncancer pain.

The diagnosis and treatment of neuropathic pain may be complicated by comorbid conditions such as sleep disturbances, depression, and anxiety. The interrelationship between the index neuropathic pain state and these comorbidities is complex: comorbid conditions exacerbate pain, and in turn, pain exacerbates the comorbid conditions. Because comorbidities can negatively impact response to pain treatment, healthcare providers should assess comorbidities as part of the diagnostic work-up, and management strategies should be designed to treat the whole patient, not just the pain. Theoretically, therapies that not only reduce pain, but also improve sleep and reduce anxiety and depression can provide multiple benefits without the risk of increased side effects inherent in combination therapy. Anticonvulsants and antidepressants have demonstrated efficacy in improving neuropathic pain and positively impacting comorbid sleep and mood disturbances. Novel anticonvulsants that can address one or more comorbidities in addition to pain may represent viable treatment options for patients with neuropathic pain.

Despite the number of patients affected by diabetic peripheral neuropathic pain (DPNP), little consensus exists about the pathophysiology, best diagnostic tools, and primary treatment choices. Theories about the causes of DPNP are inextricably linked with the causes of diabetic neuropathies, yet most patients with such neuropathies do not experience pain. The factors that differentiate patients with pain from those without remain unknown and are the subject of much research. When choosing treatment for patients with DPNP, physicians are confronted with a myriad of choices, none of which has been shown to be effective for all patients. This article reviews the evidence for these treatments and attempts to guide physicians in choosing those treatments based on evidence from well-designed clinical trials to support their use. Two agents, duloxetine and pregabalin, are formally approved by the Food and Drug Administration for the treatment of DPNP. In addition, several other agents, including the tricyclic class of antidepressants, have been effective in clinical trials. Ultimately, treatment choice must also include consideration of adverse effects, individual patient factors such as comorbidities, and often cost.

Multidrug therapy (MDT) has been widely accepted and used as a standard of practice in most areas of medical practice, including neuropathic pain. Because neuropathic pain is a new field of medical science and practice, standards for its treatment including MDT are still evolving. In this article, we present rationale and principals for the MDT of neuropathic pain based on our best understandings of the underlying mechanisms of the disease processes and the actions of drugs, the goal being to maximize benefits and minimize adverse effects. MDT for neuropathic pain is based on a comprehensive clinical neuropathic pain assessment and ongoing monitoring of the drug therapy's efficacy and adverse effects, administering one drug at the time.

The term targeted peripheral analgesics has been suggested to describe analgesics with a mechanism of action that appears to be primarily through reducing pain transmission within the peripheral nervous system. Key differences between targeted peripheral (topical) and systemic analgesics and the difference between topical and transdermal analgesics are discussed in this article. A review of the clinical conditions, which have been reported to respond to targeted peripheral analgesics, also is described in detail.

To determine the impact of the lidocaine patch 5% on distinct pain qualities associated with osteoarthritis (OA) through use of the Neuropathic Pain Scale (NPS), an assessment tool designed to assess intensity of various pain qualities (i.e.sharp, dull).Patients were enrolled in a prospective, open-label, non-randomized, parallel-group, 2-week study involving 8 clinical trial sites in the United States. Eligible patients had radiographic evidence of OA involving one or both knees and reported moderate-to-severe pain (despite prn or stable doses of analgesics) on the NPS at study enrollment. Patients on prn analgesics were discontinued from all analgesic regimens prior to study entry and received lidocaine patch 5% as monotherapy. Those on stable doses of analgesics were continued on their other analgesic regimens with no additions or dose alterations allowed other than the lidocaine patch 5% as add-on therapy. The lidocaine patch 5% was applied to the area of maximal pain, using no more than a total of 4 patches changed every 24 h. Effectiveness was measured by change from baseline to Week 2 in 4 composite measures of the NPS: NPS-10, NPS-4, NPS-8, and NPS-nonallodynia. Safety was assessed by adverse events (AEs), dermal assessment of application site(s), and skin sensory testing.In the combined patient population (n = 100), 2 weeks of treatment with lidocaine patch 5% significantly improved all 4 NPS composite measures (p0.001). Separate analyses by subgroups revealed significant improvements in all 4 composite measures for both the monotherapy group (n = 12; p0.01) and add-on therapy group (n = 88; p0.001). No treatment-related AEs were reported for the monotherapy group. In the add-on therapy group, 5 patients experienced mild-to-moderate treatment-related AEs.In patients with moderate-to-severe OA of the knee, 2 weeks of treatment with the lidocaine patch 5% significantly reduces the intensity of pain qualities as measured by all 4 NPS composite measures. Our results coincide with previously reported improvements in pain and physical function in the same patient population, as measured by the Western Ontario and McMaster Universities OA Index. Measuring the various qualities of pain appears to be a valid approach for assessing clinical outcomes in the treatment of OA pain. Pain measures such as the NPS can capture the multi-dimensional properties of a patient's pain experience and may offer clinicians the possibility to identify differential effects of analgesic treatments on various pain qualities associated with OA.

The use of botulinum toxin in the management of various neurologic and non-neurologic disorders has grown considerably over the past decade. At the same time, new information regarding the mechanism of action of these toxins has evolved allowing for a greater understanding of the versatility of these agents. Although two types of botulinum toxin (type A Botox [Allergan, Inc., Irvine, CA] and type B Myobloc [Elan Products, New York) are commercially available in the US, most studies of the use of these toxins for the management of chronic pain and headache have been completed with type A. Data from open-label and retrospective studies as well as clinical practice suggest as strongly as possible that there is a role for these agents, especially Botox, in the management of several chronic headache disorders, including chronic migraine, chronic tension-type, cervicogenic, and cluster headache. Emerging data regarding the use of these agents for so-called “analgesic-rebound” headache also appear impressive; however, as of yet, no multicenter, randomized, controlled studies for any headache type have been published that confirm the results seen in noncontrolled studies. Nevertheless, the benefit that some patients experience from this agent is impressive, and this drug appears for many to modify the disorder in a very positive manner. In a similar fashion, data for other pain states are often restricted to open-label and case study approaches; however, clinical experience and some of the available studies (even small controlled studies) suggest a role for the toxins in the management of various chronic pain states, such as myofascial pain, low back pain, and neuropathic pain. One of the greatest challenges ahead for all interested in this area is confirming the benefit seen clinically through appropriately designed multicenter, randomized, controlled studies.

Understanding the pathophysiology of a pain syndrome is helpful in selecting appropriate treatment strategies. Nociceptive pain is related to damage to tissues due to thermal, chemical, mechanical, or other types of irritants. Neuropathic pain results from injury to the peripheral or central nervous system. Common examples of neuropathic pain include postherpetic neuralgia, diabetic neuropathy, complex regional pain syndrome, and pain associated with spinal cord injuries. Nociceptive pain may have similar clinical characteristics to neuropathic pain. It is also possible for acute nociceptive pain to become neuropathic in nature, as with myofascial pain syndrome. A clear benefit of botulinum toxin therapy for treatment of neuropathic pain disorders is that it often relieves pain symptoms. Although the precise mechanism of pain relief is not completely understood, the injection of botulinum toxin may reduce various substances that sensitize nociceptors. As a result, botulinum toxin types A and B are now being actively studied in nociceptive and neuropathic pain disorders to better define their roles as analgesics.

There has been increasing interest in exploring the potential therapeutic benefit of the botulinum toxins in the management of neuropathic pain. Examples of neuropathic pain include painful diabetic polyneuropathy, postherpetic neuralgia (PHN), complex regional pain syndrome, trigeminal neuralgia and neuropathic low back pain. Other chronic pain syndromes may exhibit neuropathic features including migraine and fibromylagia but are not considered by most to be typical neuropathic pain states [1–3]. Xiao et al. in this issue of Pain Medicine report the results of their randomized controlled study evaluating the effect of subcutaneous injections of botulinum toxin type A (BOTOX) compared with lidocaine and placebo injections for the treatment of PHN [4]. As has been outlined elsewhere in this issue by Xiao et al., BOTOX is known to have analgesic properties with an increasing awareness of proposed mechanisms that underlie these analgesic benefits. Neuropathic pain is often associated with other chronic pain syndromes, which may be effectively treated with botulinum toxins, in particular, myofascial pain. Allen et al. have demonstrated that 56% of 134 patients with CRPS type 1 demonstrated evidence of myofascial pain in association with their neuropathic pain [5]. This not only confirmed that different types of pain may co-exist within the same patient and that one type of pain, e.g., neuropathic pain may lead to and become associated with another type of pain, but it led to the consideration of how these observations might lead to more effective treatment. Muscle nociceptors are known to become sensitized by substances including bradykinin and prostaglandins as well as others similar to that seen in neuropathic pain. One investigator has emphasized the role of autonomic nervous system dysfunction …

Although most acute conditions of the spine are benign and self-limited, the economic costs and disability resulting from these disorders have reached epidemic proportions in industrialized society. Recent scientific research to determine the causes of common spinal disorders, long attributed to structural abnormalities, have now implicated complex biochemical and neurophysiologic processes which may offer insights for future therapy interventions. This article reviews the functional and pathologic anatomy and correlates with current diagnostic and nonoperative management strategies for common mechanical spinal and radicular pain syndromes.

To determine if peripheral neuropathology exists among the innervation of cutaneous arterioles and arteriole-venule shunts (AVS) in fibromyalgia (FM) patients.Cutaneous arterioles and AVS receive a convergence of vasoconstrictive sympathetic innervation, and vasodilatory small-fiber sensory innervation. Given our previous findings of peripheral pathologies in chronic pain conditions, we hypothesized that this vascular location may be a potential site of pathology and/or serotonergic and norepinephrine reuptake inhibitors (SNRI) drug action.Twenty-four female FM patients and nine female healthy control subjects were enrolled for study, with 14 additional female control subjects included from previous studies. AVS were identified in hypothenar skin biopsies from 18/24 FM patient and 14/23 control subjects.Multimolecular immunocytochemistry to assess different types of cutaneous innervation in 3 mm skin biopsies from glabrous hypothenar and trapezius regions.AVS had significantly increased innervation among FM patients. The excessive innervation consisted of a greater proportion of vasodilatory sensory fibers, compared with vasoconstrictive sympathetic fibers. In contrast, sensory and sympathetic innervation to arterioles remained normal. Importantly, the sensory fibers express α2C receptors, indicating that the sympathetic innervation exerts an inhibitory modulation of sensory activity.The excessive sensory innervation to the glabrous skin AVS is a likely source of severe pain and tenderness in the hands of FM patients. Importantly, glabrous AVS regulate blood flow to the skin in humans for thermoregulation and to other tissues such as skeletal muscle during periods of increased metabolic demand. Therefore, blood flow dysregulation as a result of excessive innervation to AVS would likely contribute to the widespread deep pain and fatigue of FM. SNRI compounds may provide partial therapeutic benefit by enhancing the impact of sympathetically mediated inhibitory modulation of the excess sensory innervation.

Many chronic pain patients have multiple etiologies for their pain, and accurate characterization of pain qualities and pain relief is essential for managing their pain. The ability to utilize a validated tool for assessing pain qualities and for identifying unique analgesic therapy effects on different pain qualities may assist clinicians in devising an appropriate treatment regimen. The Neuropathic Pain Scale (NPS) is a novel pain metric for characterizing pain in 10 dimensions. The ability to differentiate among pain qualities for each patient may result in a more refined and effective choice of therapy. The three research articles in this Supplement demonstrate the utility of the NPS in chronic pain patients treated with the lidocaine patch 5%, a peripherally acting medication that is not associated with systemic accumulation of the active drug. Significant reduction in the intensity of commonly reported pain qualities in patients with neuropathic and non-neuropathic chronic pain due to low-back pain, osteoarthritis, post-herpetic neuralgia, and painful diabetic neuropathy were achieved. The NPS offers clinicians a reliable means to accurately identify pain qualities associated with each individual patient and to target and assess the efficacy of various therapeutic options on those pain components. Utilizing the NPS, the lidocaine patch 5% was effective in treating chronic pain of both neuropathic and non-neuropathic origins suggesting that a given treatment's effect on various pain qualities may be consistent across pain types.

CLUSTER HEADACHE IS almost always idiopathic, but, in rare cases, associated intracranial lesions have been found. We describe a patient who had chronic cluster headache for more than 20 years. The headache immediately resolved upon resection of a tentorial meningioma. Prior reports of clust

There has been a concerted effort by public health, regulatory, and professional groups to curtail the serious problem of prescription opioid-related misuse that emerged during the last decade. The nature of this problem was fully explicated in a recent Pain Medicine Supplement [1], and the American Academy of Pain Medicine (AAPM) has been engaged with several agencies, including the United States Food and Drug Administration (FDA), the White House Office of National Drug Control Policy, and members of Congress to create long-term solutions focusing on professional education and research. On July 25, 2012 a petition with 37 co-signers was submitted to the FDA by Physicians for Responsible Opioid Prescribing (PROP), a group of concerned healthcare professionals and scientists, requesting label changes from the FDA in connection with certain opioid products as a means to address this public health crisis [2]. Members of the AAPM leadership reviewed this document, and after due deliberation and consideration of the petitioners' points viz-a-viz the AAPM mission, current scientific and clinical evidence, and ethical concerns for patient safety and health, the Academy responded to the petition with the following submission to the FDA signed by all members of the Board of Directors. This is now a public document, and we produce it here for the benefit of AAPM members, readership, and other interested parties. Bold headings have been added to assist the reader. No other content has been changed. You can reach your own conclusions and perhaps enrich the dialog with commentary, critique, concerns, and additional thoughts through correspondence to the Editor. The Academy looks forward to constructively working with members of PROP, Congress, and others to solve the serious prescription drug problem in America. The authors make the following disclosures of honoraria and consulting fees. During the past year, Dr. Fine has …

Pain medicine is among the youngest subspecialties of medicine and is still in the midst of defining itself. In this process, it is very important to address the needs of the most vulnerable patient populations who have increased burden of illness and pharmacological intake with many potential adverse consequences; one such population is the older patient with persistent pain. The updated guidelines for the pharmacological management of persistent pain in older persons is an important step in keeping the developments in pain management in the older person known to those health care providers who are responsible for their care. Especially useful for the practicing clinicians is the very insightful overview about the general context of pain management, including the crucial role of an adequate pain assessment as the starting point. One of the challenges in publishing guidelines is the goal to be comprehensive and practical while following information from rigorous clinical trials as the gold standard. This guideline, similar to a previous guideline on this topic, is based on clinical standards in the field and on existing data that is often limited in scope and quality. The end product is necessarily a synthesis of the best available evidence [1]. Because the science of pain medicine has evolved slowly, pain guidelines in general and this one in particular are fraught with limitations. In the introductory section, it is stated that the focus is on those age 75 years and older, yet the quality of evidence in this subset of older adults is perhaps more limited than any other. It becomes difficult for the practitioner caring for these individuals who often have multiple and …