Brain reward circuitry: The overlapping neurobiology of trauma and substance use disorders.

Mental health symptoms secondary to trauma exposure and substance use disorders (SUDs) co-occur frequently in both clinical and community samples. The possibility of a shared aetiology remains an important question in translational neuroscience. Advancements in genetics, basic science, and neuroimaging have led to an improved understanding of the neural basis of these disorders, their frequent comorbidity and high rates of relapse remain a clinical challenge. This project aimed to conduct a review of the field's current understanding regarding the neural circuitry underlying posttraumatic stress disorder and SUD. A comprehensive review was conducted of available published literature regarding the shared neurobiology of these disorders, and is summarized in detail, including evidence from both animal and clinical studies. Upon summarizing the relevant literature, this review puts forth a hypothesis related to their shared neurobiology within the context of fear processing and reward cues. It provides an overview of brain reward circuitry and its relation to the neurobiology, symptomology, and phenomenology of trauma and substance use. This review provides clinical insights and implications of the proposed theory, including the potential development of novel pharmacological and therapeutic treatments to address this shared neurobiology. Limitations and extensions of this theory are discussed to provide future directions and insights for this shared phenomena.

Perspectives on the opioid crisis from pain medicine clinicians.

Patients experiencing a terminal drug related event reflect a sentinel event. If this pharmacotherapy is a widely used agent, it may be viewed as a catastrophic problem. If patients are dying from illegal drug use when the medical establishment fails them by withdrawing or minimizing their medically prescribed medication, then the burden rests with their health care providers, legislation, and insurance carriers to actively participate in a collegial fashion to achieve parity. Causing a decay in functionality in previously functional patients, may occur with appropriately prescribed opioid medications addressing non-cancer pain when withdrawing or diminishing either with or without patient consent. The members of the medical profession have diminished their prescribing of opioids for their patients out of apparent fear of reprisal, state or federal government sanctions, and other concerned groups. Diminishing former dosages or deleting the opioid medication, preferably in concert with the patient, often results in inequitable patient care. Enforcing sanctioned decreases or ceasing to prescribe from their former required/established opioid medications precipitate patient discord. In absence of opioid misuse, abuse, diversion or addiction based upon medical "guidelines" and with a poor foundation of Evidence Based Medicine the CDC guidelines, it may be masked as a true guideline reflecting a decrement of clinical judgment, wisdom, and compassion. This article also discusses the role of pharmacy chains, insurance carriers, and their pharmacy benefit managers (PBMs) contribution to this multidimensional problem. There may be a potential solution, identified in this paper, if all the associated political, medical and insurance groups work cohesively to improve patient care. This article and the CDC guidelines are not focused at hospice, palliative, end of life care pain management.

Opioid Therapy in Acute and Chronic Pain.

This is an article in the Core Entrustables in Clinical Pharmacology series that describes opioid therapy in acute and chronic pain. Opioid use during surgical procedures or anesthesia is not discussed. Basic pharmacokinetic and pharmacodynamic properties of opioids are reviewed. The safe and effective use of opioids, including clinical assessment and treatment plan, equianalgesic dosing, opioid rotation, opioid risks and side effects, and clinical adherence monitoring are discussed. Individualized opioid use can be a safe and effective component of a patient-specific multimodal treatment plan for acute or chronic pain. Adverse effects and risks can be prevented or effectively managed when anticipated and recognized. The article is followed by 4 clinical vignettes with discussions.

Primary Headache Disorders Part I- Migraine and the Trigeminal Autonomic Cephalalgias.

In Primary Headache Disorders, Part 1, we discuss three of the primary headache disorders using the headache definitions from ICHD-III (Beta): Migraine, with and without aura; its pathophysiology and treatment are discussed. We then discuss the Trigeminal Autonomic Cephalalgias (TACs), including Cluster Headache and Hemicrania Continua, two more primary headache disorders, as well as the other TAC Headaches. We discuss pathophysiology as well as diagnosis, treatment, and pharmacotherapeutic management of these headache diatheses.

Primary Headache Disorders- Part 2: Tension-type headache and medication overuse headache.

In Part 2 of Primary Headache disorders, we discuss the fourth Primary Headache Disorder, Tension-Type Headache (TTHA). We are again using the ICHD-III (Beta) definitions of such headaches, taking into consideration episodic and chronic TTHA, as well as the presence or absence of pericranial muscle tenderness. We discuss the pathophysiology and pharmacotherapeutic treatment of TTHA, and the aspects of the Myofascial Pain Syndrome that enhance and help the development of TTHA. We then discuss Medication Overuse Headache (MOH), itself a Secondary headache disorder, but one that is extremely important as it assists with the chronification of both migraine and TTHA. Finally we discuss how to manage and treat those patients with MOH. Chronic migraine, which is TTHA, Migraine as well as, in many patients, MOH, is discussed along with the treatment of this multifaceted disorder.

Responsible, Safe, and Effective Prescription of Opioids for Chronic Non-Cancer Pain: American Society of Interventional Pain Physicians (ASIPP) Guidelines.

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).Summary of Recommendations:i. Initial Steps of Opioid Therapy 1. Comprehensive assessment and documentation. (Evidence: Level I; Strength of Recommendation: Strong) 2. Screening for opioid abuse to identify opioid abusers. (Evidence: Level II-III; Strength of Recommendation: Moderate) 3. Utilization of prescription drug monitoring programs (PDMPs). (Evidence: Level I-II; Strength of Recommendation: Moderate to strong) 4. Utilization of urine drug testing (UDT). (Evidence: Level II; Strength of Recommendation: Moderate) 5. Establish appropriate physical diagnosis and psychological diagnosis if available. (Evidence: Level I; Strength of Recommendation: Strong) 6. Consider appropriate imaging, physical diagnosis, and psychological status to collaborate with subjective complaints. (Evidence: Level III; Strength of Recommendation: Moderate) 7. Establish medical necessity based on average moderate to severe (≥ 4 on a scale of 0 - 10) pain and/or disability. (Evidence: Level II; Strength of Recommendation: Moderate) 8. Stratify patients based on risk. (Evidence: Level I-II; Strength of Recommendation: Moderate) 9. Establish treatment goals of opioid therapy with regard to pain relief and improvement in function. (Evidence: Level I-II; Strength of Recommendation: Moderate) 10. Obtain a robust opioid agreement, which is followed by all parties. (Evidence: Level III; Strength of Recommendation: Moderate)ii. Assessment of Effectiveness of Long-Term Opioid Therapy 11. Initiate opioid therapy with low dose, short-acting drugs, with appropriate monitoring. (Evidence: Level II; Strength of Recommendation: Moderate) 12. Consider up to 40 morphine milligram equivalent (MME) as low dose, 41 to 90 MME as a moderate dose, and greater than 91 MME as high dose. (Evidence: Level II; Strength of Recommendation: Moderate) 13. Avoid long-acting opioids for the initiation of opioid therapy. (Evidence: Level I; Strength of Recommendation: Strong) 14. Recommend methadone only for use after failure of other opioid therapy and only by clinicians with specific training in its risks and uses, within FDA recommended doses. (Evidence: Level I; Strength of Recommendation: Strong) 15. Understand and educate the patients of the effectiveness and adverse consequences. (Evidence: Level I; Strength of Recommendation: Strong) 16. Similar effectiveness for long-acting and short-acting opioids with increased adverse consequences of long-acting opioids. (Evidence: Level I-II; Strength of recommendation: Moderate to strong) 17. Periodically assess pain relief and/or functional status improvement of ≥ 30% without adverse consequences. (Evidence: Level II; Strength of recommendation: Moderate) 18. Recommend long-acting or high dose opioids only in specific circumstances with severe intractable pain. (Evidence: Level I; Strength of Recommendation: Strong)iii. Monitoring for Adherence and Side Effects 19. Monitor for adherence, abuse, and noncompliance by UDT and PDMPs. (Evidence: Level I-II; Strength of Recommendation: Moderate to strong) 20. Monitor patients on methadone with an electrocardiogram periodically. (Evidence: Level I; Strength of Recommendation: Strong). 21. Monitor for side effects including constipation and manage them appropriately, including discontinuation of opioids when indicated. (Evidence: Level I; Strength of Recommendation: Strong)iv. Final Phase 22. May continue with monitoring with continued medical necessity, with appropriate outcomes. (Evidence: Level I-II; Strength of Recommendation: Moderate) 23. Discontinue opioid therapy for lack of response, adverse consequences, and abuse with rehabilitation. (Evidence: Level III; Strength of Recommendation: Moderate) CONCLUSIONS: These guidelines were developed based on comprehensive review of the literature, consensus among the panelists, in consonance with patient preferences, shared decision-making, and practice patterns with limited evidence, based on randomized controlled trials (RCTs) to improve pain and function in chronic non-cancer pain on a long-term basis. Consequently, chronic opioid therapy should be provided only to patients with proven medical necessity and stability with improvement in pain and function, independently or in conjunction with other modalities of treatments in low doses with appropriate adherence monitoring and understanding of adverse events.Key words: Chronic pain, persistent pain, non-cancer pain, controlled substances, substance abuse, prescription drug abuse, dependency, opioids, prescription monitoring, drug testing, adherence monitoring, diversionDisclaimer: The guidelines are based on the best available evidence and do not constitute inflexible treatment recommendations. Due to the changing body of evidence, this document is not intended to be a "standard of care."

Treatment of Neuropathic Pain with Venlafaxine: A Systematic Review.

OBJECTIVE: To investigate the efficacy of venlafaxine for neuropathic pain and review literature to determine if the medication provides adequate neuropathic pain relief. METHODS: Literature was reviewed on MEDLINE using various key words. These key words include: "venlafaxine and pain," "venlafaxine ER and pain," "venlafaxine XR and pain," "venlafaxine and neuropathic pain," "venlafaxine and neuropathy," "SSRI and neuropathic pain," "SSRI and neuropathy," "SNRI and neuropathic pain," "SNRI and neuropathy," "serotonin reuptake inhibitor and neuropathic pain," "serotonin reuptake inhibitor and neuropathy," "serotonin norepinephrine reuptake inhibitor and neuropathic pain" and "serotonin norepinephrine reuptake inhibitor and neuropathy." Using this guideline, 13 articles were reviewed. RESULTS: A total of 13 studies reviewed, which are organized by date and diagnosis. It is evident that in the majority of studies, when compared with a placebo, there was a clinical significant reduction in neuropathic pain relief when using venlafaxine. Additionally, one study showed even more significant pain relief when using higher doses of venlafaxine (at least 150 mg). However, when compared with alternative neuropathic medications, venlafaxine for the most part did not perform any better in terms of efficacy. CONCLUSION: In conclusion, venlafaxine is a safe and well-tolerated analgesic drug for the symptomatic treatment of neuropathic pain, and there is limited evidence that high-dose venlafaxine (150 mg/day) can be even more beneficial. While the present evidence is quite encouraging regarding venlafaxine's use for neuropathic pain, further research is needed to continue to expand on these findings, particularly when in consideration with other possible pharmacological agents.

A systematic review on the treatment of phantom limb pain with spinal cord stimulation.

Phantom limb pain (PLP) is a challenging chronic pain syndrome to treat with pharmacologic agents being first line of management. However, when these agents fail to provide pain relief, other interventions must be considered in a clinical setting. Spinal cord stimulation (SCS) has been shown to provide analgesia in PLP, and should be considered by clinicians. METHODS: This PRISMA systematic review analyzes the efficacy of SCS for treatment of PLP. RESULTS: After review of 12 studies, there are mixed results to base a conclusion on. DISCUSSION: While there is some evidence of efficacy, due to the relatively small number of patients in each study, further research is needed to demonstrate the benefits of SCS for PLP.

A systematic review on the impact of psychotropic drugs on electroencephalogram waveforms in psychiatry.

OBJECTIVES: It is known that psychotropic medications have an impact on the readings found in Electroencephalogram (EEG). In the field of psychiatry, there are several psychotropics utilized by clinicians. This review seeks to investigate all the available data for psychotropic drugs and their impact on EEG changes. METHODS: A systematic review of all the published and ongoing literature was conducted via PubMed. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method was used for each search. Key words for searches include 'EEG and Psychotropics', 'EEG and Mood Stabilizers', 'EEG and Clozapine', 'EEG and Bupropion', 'EEG and SSRI', 'EEG and Lamotrigine', 'EEG and Carbamazepine', 'EEG and Lithium' and 'EEG and Valproate', 'EEG and Haloperidol', 'EEG and Aripiprazole', 'EEG and Methylphenidate', 'EEG and Topiramate', 'EEG and Gabapentin' and 'EEG and Oxcarbamazepine'. After applying the inclusion criteria, 201 articles were eligible and reviewed. RESULTS: Following an extensive review of selected studies from the 201 articles, the studies indicate that each of the psychotropic medications reviewed impact alpha, beta, delta and theta waves independently and differently from each other. Additionally, certain medications, particularly haloperidol and valproic acid, have dissimilar results exemplified in all waveforms. CONCLUSIONS: This PRISMA systematic review illustrates that while there is available data on psychotropic medications and their proposed effect on EEG activity, further research is needed to confirm these findings to help allow clinical correlations to be made between the patient's response and the psychotropic agent.

Pharmacist's evolving role in the nonopioid, over-the-counter, analgesic selection process.

The pharmacist provides an integral role in pain management and treatment by focusing on the selection and evaluation of analgesic agents in a process that is patient specific, patient focused, and patient centered in a personalized care plan. Counseling patients (and the families of patients) who are using acetaminophen, aspirin, and/or nonsteroidal anti-inflammatory drugs for acute musculoskeletal pain and inflammation regarding the appropriate use of these agents is a key component of the pharmacist's overall pharmacotherapeutic role. This article reviews the importance of explaining the therapeutic and nontherapeutic effects of these agents, cautions, contraindications, dosing parameters, and the avoidance of acetaminophen/aspirin and multiple nonsteroidal anti-inflammatory drug use to patients and prescribers. The article also discusses the need to evaluate the cytochrome P450 system and the patient's pharmacotherapy and comorbid disease history to identify potential drug-mediated interactions. Evaluation of patients for comorbidities, allergies, and gastrointestinal, renal, hepatic, hematologic, and cardiovascular risks is also addressed, as are essential laboratory tests and the special needs of elderly patients.

Topical Nonsteroidal Anti-Inflammatory Drugs: The Importance of Drug, Delivery, and Therapeutic Outcome.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of pain associated with a variety of indications, including arthritic conditions, but their usefulness is often limited by dose-dependent adverse events (AEs), such as gastrointestinal disturbances, cardiovascular events, and renal toxicity. The risk of such effects could be reduced by the use of topical formulations, which offer the potential to deliver analgesic concentrations locally, at the site of inflammation, while minimizing systemic concentrations. The topical preparations currently approved in the United States are diclofenac sodium 1.5% topical solution (containing dimethyl sulfoxide as a penetration enhancer), diclofenac sodium gel 1%, and a diclofenac hydroxyethylpyrrolidine 1.3% patch. Each of these topical NSAIDs provide drug delivery to subcutaneous tissues for the management of pain associated with osteoarthritis or soft-tissue injuries. Furthermore, these formulations are not significantly associated with the systemic AEs associated with oral NSAIDs; the most common AEs associated with topical formulations are local skin reactions, which are usually mild and self-limiting. Other topical NSAID preparations approved in the European Union include ibuprofen creams and gels, ketoprofen gel, felbinac gel and cutaneous foam, and piroxicam gel. Meta-analyses have confirmed the efficacy and safety of these preparations. However, it is important to recognize that pharmacokinetic absorption from topical formulations can vary markedly, even between different formulations of the same drug, depending on the agent, the underlying disorder, and the site of application. It is therefore essential to consider the patient, the drug, and the drug delivery mechanism when selecting a topical NSAID preparation.

Management of auditory hallucinations as a sequela of traumatic brain injury: a case report and a relevant literature review.

A patient with progressively worsening auditory hallucinations and 30-year history of traumatic brain injury (TBI) was reported. To formulate a comprehensive diagnostic and treatment approach to patients with auditory sensory disturbances and other neuropsychiatric sequela of a TBI, an electronic search of the major behavioral science databases (PubMed, PsycINFO, Medline) and a textbook review were conducted to retrieve studies detailing the clinical characteristics, biological mechanisms, and therapeutic approaches to post-TBI psychosis. Additional references were incorporated from the bibliographies of the retrieved articles. Although infrequent, auditory hallucinations is a debilitating complication of TBI that can manifest itself 4-5 years after the occurrence of TBI. Because the age range of TBI survivors is 15-24 years, and the chance of developing post-TBI psychosis is reported to be up to 20%, this chronic neuropsychiatric complication and the available treatment options warrant close scrutiny from the clinical and the biomedical research community. Our case report and literature review demonstrates a clear need for a large, well-designed randomized trials to compare properties and efficacies of different, available, and promising pharmacotherapy agents for the treatment of post-TBI psychosis.

Painful boney metastases.

Up to 90% of patients with metastatic or advanced stage cancer will experience significant cancer-related pain. Approximately half or more of patients diagnosed with cancer may experience bone pain. It has been estimated that tumor metastases to the skeleton affects roughly 400,000 US citizens annually. Carcinoma from breast, lung, and prostate cancers account for approximately 80% of secondary metastatic bone disease. Bone metastases may cause devastating clinical complications associated with dramatic reductions in quality of life, mobility, and independence, as well as excruciating refractory pain. Associated complications from osseous metastases also present a substantial economic burden. Currently, there are still a significantly high number of patients suffering with unrelieved pain from osseous metastases. Treatments for painful osseous metastases may not only diminish pain but also may improve quality of life and independence/mobility, and reduce skeletal morbidity, potential pathologic fractures, spinal cord compression, and other "skeletal-related events." Treatment strategies for painful osseous metastases include the following: systemic analgesics, intrathecal analgesics, glucocorticoids, radiation (external beam radiation, radiopharmaceuticals), ablative techniques (radiofrequency ablation and cryoablation), bisphosphonates, chemotherapeutic agents, inhibitors of RANKL-RANK interaction (eg, denosumab), hormonal therapies, interventional techniques (eg, kyphoplasty), and surgical approaches. Although the mechanisms underlying the development of bone metastases remain incompletely understood, there appears to be important bi-directional interactions between the tumor and the bone microenvironment. A greater understanding of the pathophysiology of painful osseous metastases may lead to better and more selective targeted analgesic therapy. Additionally, potential future therapeutic approaches to painful osseous metastases may revolutionize approaches to analgesia for this condition, leading to optimal outcomes with maximal pain relief and minimal adverse effects.

Options for treating postherpetic neuralgia in the medically complicated patient.

Patients with postherpetic neuralgia (PHN) are often of advanced age or immunocompromised and likely to have ≥1 comorbid medical condition for which they receive ≥1 medication (polypharmacy). Comorbidities affecting renal or hepatic function can alter pharmacokinetics, thereby impacting the efficacy or tolerability of PHN analgesic therapies. Cardiovascular, cerebrovascular, or psychiatric comorbidities may increase patient vulnerability to potential adverse events associated with some PHN analgesic therapies. Because PHN is a localized condition, localized therapy with a topical analgesic (lidocaine patch 5% and capsaicin 8% patch or cream) may provide adequate efficacy while mitigating the risk of systemic adverse events compared with oral analgesics (eg, tricyclic antidepressants, anticonvulsants, opioids). However, combined therapy with a topical and an oral analgesic or with >1 oral analgesic may be needed for optimal pain management in some patients. This review summarizes how comorbidities and concomitant medications should be taken into account when selecting among available pharmacotherapies for PHN and provides recommendations for the selection of therapies that will provide analgesia while minimizing the risk of adverse events.

The pharmacology of topical analgesics.

Pain management of patients continues to pose challenges to clinicians. Given the multiple dimensions of pain--whether acute or chronic, mild, moderate, or severe, nociceptive or neuropathic--a multimodal approach may be needed. Fortunately, clinicians have an array of nonpharmacologic and pharmacologic treatment choices; however, each modality must be chosen carefully, because some often used oral agents are associated with safety and tolerability issues that restrict their use in certain patients. In particular, orally administered nonsteroidal antiinflammatory drugs, opioids, antidepressants, and anticonvulsants are known to cause systemic adverse effects in some patients. To address this problem, a number of topical therapies in various therapeutic classes have been developed to reduce systemic exposure and minimize the risks of patients developing adverse events. For example, topical nonsteroidal anti-inflammatory drug formulations produce a site-specific effect (ie, cyclo-oxygenase inhibition) while decreasing the systemic exposure that may lead to undesired effects in patients. Similarly, derivatives of acetylsalicylic acid (ie, salicylates) are used in topical analgesic formulations that do not significantly enter the patient's systemic circulation. Salicylates, along with capsaicin, menthol, and camphor, compose the counterirritant class of topical analgesics, which produce analgesia by activating and then desensitizing epidermal nociceptors. Additionally, patches and creams that contain the local anesthetic lidocaine, alone or co-formulated with other local anesthetics, are also used to manage patients with select acute and chronic pain states. Perhaps the most common topical analgesic modality is the cautious application of cutaneous cold and heat. Such treatments may decrease pain not by reaching the target tissue through systemic distribution, but by acting more directly on the affected tissue. Despite the tolerability benefits associated with avoiding systemic circulation, topically applied analgesics are associated with application-site reactions in patients, such as dryness, erythema, burning, and discoloration. Furthermore, some adverse events that have been observed in patients may be suggestive of some degree of systemic exposure. This article reviews the mechanisms of action, pharmacokinetics, and tolerability of topical treatments for the management of patient pain.