Medications which bind to opioid receptors are increasingly being prescribed for the treatment of multiple and diverse chronic painful conditions. Their use for acute pain or terminal pain is well accepted. Their role in the long-term treatment of chronic noncancer pain is, however, controversial for many reasons. One of the primary reasons is the well-known phenomenon of psychological addiction that can occur with the use of these medications. Abuse and diversion of these medications is a growing problem as the availability of these medications increases and this public health issue confounds their clinical utility. Also, the extent of their efficacy in the treatment of pain when utilized on a chronic basis has not been definitively proven. Lastly, the role of opioids in the treatment of chronic pain is also influenced by the fact that these potent analgesics are associated with a significant number of side effects and complications. It is these phenomena that are the focus of this review. Common side effects of opioid administration include sedation, dizziness, nausea, vomiting, constipation, physical dependence, tolerance, and respiratory depression. Physical dependence and addiction are clinical concerns that may prevent proper prescribing and in turn inadequate pain management. Less common side effects may include delayed gastric emptying, hyperalgesia, immunologic and hormonal dysfunction, muscle rigidity, and myoclonus. The most common side effects of opioid usage are constipation (which has a very high incidence) and nausea. These 2 side effects can be difficult to manage and frequently tolerance to them does not develop; this is especially true for constipation. They may be severe enough to require opioid discontinuation, and contribute to under-dosing and inadequate analgesia. Several clinical trials are underway to identify adjunct therapies that may mitigate these side effects. Switching opioids and/or routes of administration may also provide benefits for patients. Proper patient screening, education, and preemptive treatment of potential side effects may aid in maximizing effectiveness while reducing the severity of side effects and adverse events. Opioids can be considered broad spectrum analgesic agents, affecting a wide number of organ systems and influencing a large number of body functions. Key words: Opioids, morphine, methadone, fentsnyl, oxycodone, hydrocodone, xymorphone, codeine, adverse events, narcotics, side effects, constipation, sedation, hearing loss, tolerance, addiction, hyperalgesia

Background: Opioid use, abuse, and adverse consequences, including death, have escalated at an alarming rate since the 1990s. In an attempt to control opioid abuse, numerous regulations and guidelines for responsible opioid prescribing have been developed by various organizations. However, the US opioid epidemic is continuing and drug dose deaths tripled during 1999 to 2015. Recent data show a continuing increase in deaths due to natural and semisynthetic opioids, a decline in methadone deaths, and an explosive increase in the rates of deaths involving other opioids, specifically heroin and illicit synthetic fentanyl. Contrary to scientific evidence of efficacy and negative recommendations, a significant proportion of physicians and patients (92%) believe that opioids reduce pain and a smaller proportion (57%) report better quality of life. In preparation of the current guidelines, we have focused on the means to reduce the abuse and diversion of opioids without jeopardizing access for those patients suffering from non-cancer pain who have an appropriate medical indication for opioid use. Objectives: To provide guidance for the prescription of opioids for the management of chronic non-cancer pain, to develop a consistent philosophy among the many diverse groups with an interest in opioid use as to how appropriately prescribe opioids, to improve the treatment of chronic non-cancer pain and to reduce the likelihood of drug abuse and diversion. These guidelines are intended to provide a systematic and standardized approach to this complex and difficult arena of practice, while recognizing that every clinical situation is unique. Methods: The methodology utilized included the development of objectives and key questions. The methodology also utilized trustworthy standards, appropriate disclosures of conflicts of interest, as well as a panel of experts from various specialties and groups. The literature pertaining to opioid use, abuse, effectiveness, and adverse consequences was reviewed, with a best evidence synthesis of the available literature, and utilized grading for recommendation as described by the Agency for Healthcare Research and Quality (AHRQ).

The purpose of this study was to examine opioid and endocannabinoid mechanisms of exercise-induced hypoalgesia (EIH). Fifty-eight men and women (mean age = 21 yrs) completed three sessions. During the first session, participants were familiarized with the temporal summation of heat pain and pressure pain protocols. In the exercise sessions, following double-blind administration of either an opioid antagonist (50 mg naltrexone) or placebo, participants rated the intensity of heat pulses and indicated their pressure pain thresholds (PPT) and ratings (PPR) before and after 3 minutes of submaximal isometric exercise. Blood was drawn before and after exercise. Results indicated circulating concentrations of two endocannabinoids, N-arachidonylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) as well as related lipids oleoylethanolamide (OEA), palmitoylethanolamide (PEA), N-docsahexaenoylethanolamine (DHEA), and 2-oleoylglycerol (2-OG) increased significantly (p < 0.05) following exercise. PPT increased significantly (p < 0.05) while PPR decreased significantly (p < 0.05) following exercise. Also, temporal summation ratings were significantly lower (p < 0.05) following exercise. These changes in pain responses did not differ between placebo or naltrexone conditions (p > 0.05). A significant association was found between EIH and DHEA. These results suggest involvement of a non-opioid mechanism in EIH following isometric exercise.

Background: Chronic axial spinal pain is one of the major causes of significant disability and health care costs, with facet joints as one of the proven causes of pain. Objective: To provide evidence-based guidance in performing diagnostic and therapeutic facet joint interventions. Methods: The methodology utilized included the development of objectives and key questions with utilization of trustworthy standards. The literature pertaining to all aspects of facet joint interventions, was reviewed, with a best evidence synthesis of available literature and utilizing grading for recommendations. Summary of Evidence and Recommendations: Non-interventional diagnosis: • The level of evidence is II in selecting patients for facet joint nerve blocks at least 3 months after onset and failure of conservative management, with strong strength of recommendation for physical examination and clinical assessment. • The level of evidence is IV for accurate diagnosis of facet joint pain with physical examination based on symptoms and signs, with weak strength of recommendation. Imaging: • The level of evidence is I with strong strength of recommendation, for mandatory fluoroscopic or computed tomography (CT) guidance for all facet joint interventions. • The level of evidence is III with weak strength of recommendation for single photon emission computed tomography (SPECT) . • The level of evidence is V with weak strength of recommendation for scintography, magnetic resonance imaging (MRI), and computed tomography (CT) . Interventional Diagnosis: Lumbar Spine: • The level of evidence is I to II with moderate to strong strength of recommendation for lumbar diagnostic facet joint nerve blocks. • Ten relevant diagnostic accuracy studies with 4 of 10 studies utilizing controlled comparative local anesthetics with concordant pain relief criterion standard of ≥ 80% were included. • The prevalence rates ranged from 27% to 40% with false-positive rates of 27% to 47%, with ≥ 80% pain relief.Limitations: The limitations of these guidelines include a paucity of high-quality studies in the majority of aspects of diagnosis and therapy. Conclusions: These facet joint interventions guidelines were prepared with a comprehensive review of the literature with methodologic quality assessment with determination of level of evidence and strength of recommendations Key words: Chronic spinal pain, interventional techniques, diagnostic blocks, therapeutic interventions, facet joint nerve blocks, intraarticular injections, radiofrequency neurolysis

Neuropathic pain disorders are usually characterized by spontaneous ongoing or intermittent symptoms, stimulus-evoked positive sensory phenomena, and negative sensory phenomena. Spontaneous individual subject specific phenomena are identified in the neurologic history and are quantifiable by means of self-reported neuropathic pain symptoms tools such as scales, inventories, and questionnaires. Negative and positive sensory phenomena are assessed by the neurologic bedside examination and quantitative sensory testing (QST), which refers to psychophysical tests of sensory perception during the administration of stimuli with predetermined physical properties and following specific protocols. QST is able to capture and quantify stimulus-evoked negative and positive sensory phenomena, and as such should become standard if not a critical tool in neuropathic pain research and practice. Although the advent of anatomic and functional imaging modalities is revolutionizing our understanding of the mechanisms of neuropathic pain, only by anchoring such test results to individual subjects' own perceptions via QST can they provide meaningful information about neuropathic pain, which is based on perceptual experience. To yield useful results, QST requires a cooperative subject and carefully standardized methods, including standardization of the stimulus parameters as well as the testing environment, instructions, and evaluation methods. This manuscript provides a concise review of fundamental concepts necessary for understanding the role of QST in the process of eliciting information about sensory abnormalities associated with neuropathic pain and the place of that information in analysis of pain mechanisms. Together with the companion manuscript, this review provides definitions that should help further the use of QST as a diagnostic tool as well.

Background:The efficacy of epidural and facet joint injections has been assessed utilizing multiple solutions including saline, local anesthetic, steroids, and others. The responses to these various solutions have been variable and have not been systematically assessed with long-term follow-ups.Methods:Randomized trials utilizing a true active control design were included. The primary outcome measure was pain relief and the secondary outcome measure was functional improvement. The quality of each individual article was assessed by Cochrane review criteria, as well as the criteria developed by the American Society of Interventional Pain Physicians (ASIPP) for assessing interventional techniques. An evidence analysis was conducted based on the qualitative level of evidence (Level I to IV).Results:A total of 31 trials met the inclusion criteria. There was Level I evidence that local anesthetic with steroids was effective in managing chronic spinal pain based on multiple high-quality randomized controlled trials. The evidence also showed that local anesthetic with steroids and local anesthetic alone were equally effective except in disc herniation, where the superiority of local anesthetic with steroids was demonstrated over local anesthetic alone.Conclusion:This systematic review showed equal efficacy for local anesthetic with steroids and local anesthetic alone in multiple spinal conditions except for disc herniation where the superiority of local anesthetic with steroids was seen over local anesthetic alone.

of Background Data: The high prevalence of chronic persistent neck pain not only leads to disability but also has a significant economic, societal, and health impact. Among multiple modalities of treatments prescribed in the management of neck and upper extremity pain, surgical, interventional and conservative modalities have been described. Cervical epidural injections are also common modalities of treatments provided in managing neck and upper extremity pain. They are administered by either an interlaminar approach or transforaminal approach.Objectives: To determine the long-term efficacy of cervical interlaminar and transforaminal epidural injections in the treatment of cervical disc herniation, spinal stenosis, discogenic pain without facet joint pain, and post-surgery syndrome. Materials and Methods:The literature search was performed from 1966 to April 2014 utilizing data from PubMed, Cochrane Library, US National Guideline Clearinghouse, previous systematic reviews, and crossreferences. The evidence was assessed based on best evidence synthesis with Level I to Level V.Results: There were 7 manuscripts meeting inclusion criteria. Of these, 4 assessed the role of interlaminar epidural injections for managing disc herniation or radiculitis, and 3 assessed these injections for managing central spinal stenosis, discogenic pain without facet joint pain, and post surgery syndrome. There were 4 high quality manuscripts. A qualitative synthesis of evidence showed there is Level II evidence for each etiology category. The evidence is based on one relevant, high quality trial supporting the efficacy of cervical interlaminar epidural injections for each particular etiology. There were no randomized trials available assessing the efficacy of cervical transforaminal epidural injections. Conclusion:This systematic review with qualitative best evidence synthesis shows Level II evidence for the efficacy of cervical interlaminar epidural injections with local anesthetic with or without steroids, based on at least one high-quality relevant randomized control trial in each category for disc herniation, discogenic pain without facet joint pain, central spinal stenosis, and post-surgery syndrome.

This study provides preliminary evidence that psychosocial variables, such as the family environment and mood states, can affect both pain sensitivity and the ability to modulate pain through exercise-induced hypoalgesia.