Pain medicine training resources: Module 7

Abstract
Migraine is the most common cause of headache during pregnancy. Pregnancy increases risk for many causes of headache, including pathologic vascular processes. Headache associated with neurologic signs or symptoms or that is progressive and refractory to treatment; acute in onset; and severe, postural, or different from typical headaches should be evaluated. Work-up should include cerebral and cerebrovascular imaging and monitoring for hypertension. Acetaminophen is first-line symptomatic treatment during pregnancy, and evidence supports triptans rather than butalbital combination analgesics as second-line treatment. Propranolol is preferred preventive treatment, and amitriptyline and verapamil may be considered. Treatment of migraine during lactation is less restrictive than during pregnancy.

Abstract
Background: Interest in the use of cannabis and cannabinoids to treat chronic non-cancer pain is increasing, because of their potential to reduce opioid dose requirements. We aimed to investigate cannabis use in people living with chronic non-cancer pain who had been prescribed opioids, including their reasons for use and perceived effectiveness of cannabis; associations between amount of cannabis use and pain, mental health, and opioid use; the effect of cannabis use on pain severity and interference over time; and potential opioid-sparing effects of cannabis.

Methods: The Pain and Opioids IN Treatment study is a prospective, national, observational cohort of people with chronic non-cancer pain prescribed opioids. Participants were recruited through community pharmacies across Australia, completed baseline interviews, and were followed up with phone interviews or self-complete questionnaires yearly for 4 years. Recruitment took place from August 13, 2012, to April 8, 2014. Participants were asked about lifetime and past year chronic pain conditions, duration of chronic non-cancer pain, pain self-efficacy, whether pain was neuropathic, lifetime and past 12-month cannabis use, number of days cannabis was used in the past month, and current depression and generalised anxiety disorder. We also estimated daily oral morphine equivalent doses of opioids. We used logistic regression to investigate cross-sectional associations with frequency of cannabis use, and lagged mixed-effects models to examine temporal associations between cannabis use and outcomes.

Findings: 1514 participants completed the baseline interview and were included in the study from Aug 20, 2012, to April 14, 2014. Cannabis use was common, and by 4-year follow-up, 295 (24%) participants had used cannabis for pain. Interest in using cannabis for pain increased from 364 (33%) participants (at baseline) to 723 (60%) participants (at 4 years). At 4-year follow-up, compared with people with no cannabis use, we found that participants who used cannabis had a greater pain severity score (risk ratio 1·14, 95% CI 1·01-1·29, for less frequent cannabis use; and 1·17, 1·03-1·32, for daily or near-daily cannabis use), greater pain interference score (1·21, 1·09-1·35; and 1·14, 1·03-1·26), lower pain self-efficacy scores (0·97, 0·96-1·00; and 0·98, 0·96-1·00), and greater generalised anxiety disorder severity scores (1·07, 1·03-1·12; and 1·10, 1·06-1·15). We found no evidence of a temporal relationship between cannabis use and pain severity or pain interference, and no evidence that cannabis use reduced prescribed opioid use or increased rates of opioid discontinuation.

Interpretation: Cannabis use was common in people with chronic non-cancer pain who had been prescribed opioids, but we found no evidence that cannabis use improved patient outcomes. People who used cannabis had greater pain and lower self-efficacy in managing pain, and there was no evidence that cannabis use reduced pain severity or interference or exerted an opioid-sparing effect. As cannabis use for medicinal purposes increases globally, it is important that large well designed clinical trials, which include people with complex comorbidities, are conducted to determine the efficacy of cannabis for chronic non-cancer pain.

Funding: National Health and Medical Research Council and the Australian Government.

Abstract
There has been a recent increase in public and professional concern about the prescription of strong prescription opioids for pain. Despite this concern, research to date has been limited because of a number of factors such as small sample sizes, exclusion of people with complex comorbidities, and studies of short duration. The Pain and Opioids IN Treatment is a 2-year prospective cohort study of 1500 people prescribed with pharmaceutical opioids for their chronic pain. This article provides an overview of the demographic and clinical characteristics of the cohort using the baseline data of 1514 community-based people across Australia. Participants had been in pain for a period of 10 years and had been on prescription opioids for approximately 4 years. One in 10 was on a daily morphine equivalent dose of ≥200 mg. Employment and income levels were low, and two-thirds of the sample reported that their pain had impacted on their employment status. Approximately 50% screened positive for current moderate-to-severe depression, and 1 in 5 had made a lifetime suicide attempt. There were a number of age-related differences. The younger groups experienced higher levels of pain and pain interference, more mental health and substance use issues, and barriers to treatment, compared with the older group. This study found that the people who have been prescribed strong opioids for chronic pain have very complex demographic and clinical profiles. Major age-related differences in the experiences of pain, coping, mental health, and substance use suggest the necessity of differential approaches to treatment.

Abstract
Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic features (SUNA) are described, although SUNA is rarely reported. The phenotype of SUNCT and SUNA was characterized from a large series of patients (43 SUNCT, 9 SUNA). Three attack types were identified: stabs, groups of stabs and saw-tooth attacks. The mean duration of stabs was 58 s (1-600 s); stab groups, 396 s (10-1200 s); and saw-tooth, 1160 s (5-12 000s). The attack frequency was a mean of 59 attacks/day (2-600), and this depended largely on the type of attack. The pain was orbital, supraorbital or temporal in 38 (88%) SUNCT and 7 (78%) SUNA, and also occurred in the retro-orbital region, side, top, back of head, second and third trigeminal divisions, teeth, neck and ear. All SUNCT patients had conjunctival injection and tearing. Two SUNA patients had conjunctival injection, four had tearing, but none had both. Other cranial autonomic symptoms included nasal blockage, rhinorrhoea, eyelid oedema, facial sweating/flushing and ear flushing. Cutaneous stimuli triggered attacks in 74% of SUNCT but only in 22% of SUNA patients. The majority (95% SUNCT and 89% SUNA) had no refractory period between attacks. For SUNCT 58% and for SUNA 56% of patients were agitated with the attacks. We propose a new set of diagnostic criteria for these syndromes to better encompass the clinical presentations and which include a wider range of attack length, wider trigeminal pain distribution, cutaneous triggering and lack of refractory period.

Abstract
Purpose of review: Migraine is a primary headache disorder and one of the most common and disabling neurological diseases worldwide. Genome-wide association studies have identified ≈40 genetic loci associated with migraine. How these and other genetic findings are used to expand our knowledge on the pathophysiological mechanism of common migraine and rare migraine variants will be discussed.

Recent findings: The genetic load, based on common polygenic variation, is higher in familial migraine cases than in nonfamilial cases, and higher for migraine with aura and hemiplegic migraine. Migraine shares common genetic variant risks with depression. Specific clinical features of common migraine seem to be determined by genetic factors. A stronger family history of migraine is associated with lower age-at-onset, higher frequency and number of medication days and the migraine with aura subtype. Mild hemiplegic migraine is likely caused by complex polygenic interaction of multiple gene variants and environmental factors, like in common migraine subtypes. Phenotypical features in hemiplegic migraine patients may guide physicians in providing adequate genetic counseling.

Summary: Integration of genetic, phenotypic and epigenetic data will help to identify the biological mechanisms by which genetic factors contribute to migraine pathogenesis. Recent studies show the impact of genetics on clinical features and comorbidities in migraine and may guide clinicians to an adequate genetic advice for patients.

Abstract
Background: There is increasing debate about cannabis use for medical purposes, including for symptomatic treatment of chronic pain. We investigated patterns and correlates of cannabis use in a large community sample of people who had been prescribed opioids for chronic non-cancer pain.

Methods: The POINT study included 1514 people in Australia who had been prescribed pharmaceutical opioids for chronic non-cancer pain. Data on cannabis use, ICD-10 cannabis use disorder and cannabis use for pain were collected. We explored associations between demographic, pain and other patient characteristics and cannabis use for pain.

Results: One in six (16%) had used cannabis for pain relief, 6% in the previous month. A quarter reported that they would use it for pain relief if they had access. Those using cannabis for pain on average were younger, reported greater pain severity, greater interference from and poorer coping with pain, and more days out of role in the past year. They had been prescribed opioids for longer, were on higher opioid doses, and were more likely to be non-adherent with their opioid use. Those using cannabis for pain had higher pain interference after controlling for reported pain severity. Almost half (43%) of the sample had ever used cannabis for recreational purposes, and 12% of the entire cohort met criteria for an ICD-10 cannabis use disorder.

Conclusions: Cannabis use for pain relief purposes appears common among people living with chronic non-cancer pain, and users report greater pain relief in combination with opioids than when opioids are used alone.

Abstract
Postoperative pain is an important clinical problem that has received increasing attention in recent years. However, pain following craniotomy has been a comparatively neglected topic; this review seeks to redress this imbalance. A brief overview of the anatomy of the skull and its linings is given, with particular reference to innervation. The various approaches for craniotomies are classified, with their association with acute and long-term effects on analgesic requirements. A comprehensive search of the literature was undertaken to ascertain the incidence of acute pain post craniotomy and current thoughts on pharmacological management, touching briefly on pre-emptive treatment. Also discussed is the much neglected but nevertheless real incidence of chronic pain following craniotomy and its underlying pathogenesis, prevention and treatment.

Abstract
Background: Migraine is one of the most frequent disabling neurological conditions with a major impact on the patients' quality of life.

Objectives: To give evidence-based or expert recommendations for the different drug treatment procedures in the particular migraine syndromes based on a literature search and the consensus of an expert panel.

Methods: All available medical reference systems were screened for the range of clinical studies on migraine with and without aura and on migraine-like syndromes. The findings in these studies were evaluated according to the recommendations of the European Federation of Neurological Societies (EFNS) resulting in level A, B, or C recommendations and good practice points.

Recommendations: For the acute treatment of migraine attacks, oral non-steroidal antiinflammatory drug (NSAID) and triptans are recommended. The administration should follow the concept of stratified treatment. Before intake of NSAID and triptans, oral metoclopramide or domperidone is recommended. In very severe attacks, intravenous acetylsalicylic acid or subcutaneous sumatriptan are drugs of first choice. Status migrainosus can be treated by cortoicosteroids, although this is not universally held to be helpful, or dihydroergotamine. For the prophylaxis of migraine, betablockers (propranolol and metoprolol) flunarizine, valproic acid, and topiramate are drugs of first choice. Drugs of second choice for migraine prophylaxis include amitriptyline, naproxen, petasites, and bisoprolol.

Abstract
Purpose of review: The purpose of the review is to describe what is currently known about the mechanisms, incidence and risk factors for acute and chronic postcraniotomy pain. The review will also summarize the evidence supporting the prevention and management of acute and chronic postcraniotomy pain.

Recent findings: Current studies suggest acute and chronic pain is common in patients after craniotomy. Surgical and patient factors may influence the incidence and severity of pain and a multimodal approach to acute postcraniotomy pain is recommended. Although codeine and tramadol are frequently used in the postoperative period, research suggests morphine provides superior efficacy with a good safety profile. Local anesthesia with nerve blocks has not been shown to consistently reduce acute postoperative pain, though it has recently been demonstrated to dramatically reduce the incidence of chronic pain. Despite this, little is known about the mechanisms, prevention and treatment of chronic postcraniotomy pain.

Summary: Acute and chronic pain following craniotomy is frequent and underrecognized. Several surgical and patient risk factors predispose patients to pain following neurosurgery. Further research is needed to determine the mechanisms, predictors, prevention and optimal treatment of acute and chronic pain following craniotomy.

Abstract
Cluster headache is a trigeminal autonomic cephalalgia characterised by extremely painful, strictly unilateral, short-lasting headache attacks accompanied by ipsilateral autonomic symptoms or the sense of restlessness and agitation, or both. The severity of the disorder has major effects on the patient's quality of life and, in some cases, might lead to suicidal ideation. Cluster headache is now thought to involve a synchronised abnormal activity in the hypothalamus, the trigeminovascular system, and the autonomic nervous system. The hypothalamus appears to play a fundamental role in the generation of a permissive state that allows the initiation of an episode, whereas the attacks are likely to require the involvement of the peripheral nervous system. Triptans are the most effective drugs to treat an acute cluster headache attack. Monoclonal antibodies against calcitonin gene-related peptide, a crucial neurotransmitter of the trigeminal system, are under investigation for the preventive treatment of cluster headache. These studies will increase our understanding of the disorder and perhaps reveal other therapeutic targets.

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Abstract
Calcitonin gene-related peptide (CGRP) is a 37-amino acid peptide found primarily in the C and Aδ sensory fibers arising from the dorsal root and trigeminal ganglia, as well as the central nervous system. Calcitonin gene-related peptide was found to play important roles in cardiovascular, digestive, and sensory functions. Although the vasodilatory properties of CGRP are well documented, its somatosensory function regarding modulation of neuronal sensitization and of enhanced pain has received considerable attention recently. Growing evidence indicates that CGRP plays a key role in the development of peripheral sensitization and the associated enhanced pain. Calcitonin gene-related peptide is implicated in the development of neurogenic inflammation and it is upregulated in conditions of inflammatory and neuropathic pain. It is most likely that CGRP facilitates nociceptive transmission and contributes to the development and maintenance of a sensitized, hyperresponsive state not only of the primary afferent sensory neurons but also of the second-order pain transmission neurons within the central nervous system, thus contributing to central sensitization as well. The maintenance of a sensitized neuronal condition is believed to be an important factor underlying migraine. Recent successful clinical studies have shown that blocking the function of CGRP can alleviate migraine. However, the mechanisms through which CGRP may contribute to migraine are still not fully understood. We reviewed the role of CGRP in primary afferents, the dorsal root ganglion, and in the trigeminal system as well as its role in peripheral and central sensitization and its potential contribution to pain processing and to migraine.

Abstract
Introduction: Patients with chronic headache who consume large amounts of analgesics are often encountered in clinical practice. Excessive intake of analgesics is now considered to be a cause, rather than simply a consequence, of frequent headaches, and as such the diagnosis "medication-overuse headache" (MOH) has been formulated. Despite the prevalence and clinical impact of MOH, the pathophysiology behind this disorder remains unclear and specific mechanism-based treatment options are lacking.

Discussion: Although most acute headache treatments have been alleged to cause MOH, here we conclude from the literature that opioids are a particularly problematic drug class consistently associated with worsening headache. MOH may not be a single entity, as each class of drug implicated may cause MOH via a different mechanism. Recent evidence indicates that chronic opioid administration may exacerbate pain in the long term by activating toll-like receptor-4 on glial cells, resulting in a pro-inflammatory state that manifests clinically as increased pain. Thus, from the available evidence it seems opioid-overuse headache is a phenomenon similar to opioid-induced hyperalgesia, which derives from a cumulative interaction between central sensitisation, due to repeated activation of nociceptive pathways by recurrent headaches, and pain facilitation due to glial activation.

Conclusion: Treatment strategies directed at inhibiting glial activation may be of benefit alongside medication withdrawal in the management of MOH.

Abstract
Objective: Our aim was to systematically review and meta-analyze the effectiveness of therapeutic patient education for migraine.

Methods: A literature search of multiple electronic databases (MEDLINE, EMBASE, PEDro, CINAHL, and PsychINFO) was conducted to identify randomized control trials (RCTs) published in the English and Spanish languages up to and including May 2013. Two reviewers independently selected the studies, conducted the quality assessment (Delphi list), and extracted the results. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses method was used throughout the systematic review and meta-analysis. Standardized mean difference (SMD) and 95% confidence intervals (CIs) were calculated for relevant outcome measures (headache frequency, headache disability, self-efficacy, depressive symptoms, and quality of life) and pooled in a meta-analysis using the random effects model.

Results: Fourteen RCTs were included in the systematic review. Only nine studies were included in the meta-analysis. The median quality score was 6.14 ± 1.29 (range: 5-9). There was strong-moderate evidence for intermediate-term effectiveness of therapeutic patient education on headache frequency (five studies: N = 940, SMD = -0.24, 95% CI of -0.48 to -0.01, P = 0.03), headache disability (four studies: N = 799, SMD = -1.02, 95% CI of -1.95 to -0.08, P = 0.03), and quality of life (three studies: N = 674, SMD = 0.36, 95% CI of 0.05-0.67, P = 0.02). There was no evidence for either short-term or intermediate-term effectiveness of therapeutic patient education on self-efficacy or depressive symptoms.

Conclusion: This systematic review revealed strong-moderate evidence for intermediate-term effectiveness of therapeutic patient education for migraine. Further high-quality RCTs are required for conclusive determination of its effectiveness.

Abstract
The review is devoted to the complex relationship between headache and sleep disorders. The shared neuroanatomical structures of the nervous system involved in pain perception and sleep are shown, and mechanisms of comorbidity between headaches and sleep disorders are considered. Various types of headaches in the continuum of the sleep-wake cycle are described. Both pharmacological and non-pharmacological approaches to treatment are examined in detail, with the biochemical basis of the drug action.

Abstract
Migraine is a lifelong condition that disproportionately affects women and, if not effectively managed, can lead to significant disability. It is important for clinicians to have a good understanding of the impact of the hormonal fluctuations that occur throughout a female migraineur's life, so that appropriate, stratified therapies can be implemented. In doing so, whether it is migraine onset at menarche in an adolescent young woman, or migraine worsening in a perimenopausal female migraineur, quality of life can be ensured.

Abstract
Vestibular migraine presents with attacks of spontaneous or positional vertigo, head motion-induced vertigo, and visual vertigo lasting 5 minutes to 3 days. The recent classification of vestibular migraine, jointly proposed by the Bárány Society and the International Headache Society, allows identification of vestibular migraine and probable vestibular migraine based on explicit criteria. The diagnosis is based on symptom type, severity and duration, a history of migraine, temporal association of migraine symptoms with vertigo attacks, and exclusion of other causes. Because headache is often absent during acute attacks, other migraine features such as photophobia or auras have to be specifically inquired about. During acute attacks, one may find central spontaneous or positional nystagmus, and less commonly, unilateral vestibular hypofunction. In the symptom-free interval, vestibular testing adds little to the diagnosis as findings are mostly minor and nonspecific. The pathophysiology of vestibular migraine is unknown, but several mechanisms link the trigeminal system, which is activated during migraine attacks, and the vestibular system. Treatment includes antiemetics for severe acute attacks, pharmacological migraine prophylaxis, and lifestyle changes.

Abstract
Background: Updated guidelines for the preventive treatment of episodic migraine have been issued by the American Headache Society (AHS) and the American Academy of Neurology (AAN). We summarize key 2012 guideline recommendations and changes from previous guidelines. We review the characteristics, methods, consistency, and quality of the AHS/AAN guidelines in comparison with recently issued guidelines from other specialty societies.

Methods: To accomplish this, we reviewed the AHS/AAN guidelines and identified comparable recent guidelines through a systematic MEDLINE search. We extracted key data, and summarized and compared the key recommendations and assessed quality using the Appraisal of Guidelines Research and Evaluation-II (AGREE-II) tool. We identified 2 additional recent guidelines for migraine prevention from the Canadian Headache Society and the European Federation of Neurological Societies. All of the guidelines used structured methods to locate evidence and linked recommendations with assessment of the evidence, but they varied in the methods used to derive recommendations from that evidence.

Results: Overall, the 3 guidelines were consistent in their recommendations of treatments for first-line use. All rated topiramate, divalproex/sodium valproate, propranolol, and metoprolol as having the highest level of evidence. In contrast, recommendations diverged substantially for gabapentin and feverfew. The overall quality of the guidelines ranged from 2 to 6 out of 7 on the AGREE-II tool.

Conclusion: The AHS/AAN and Canadian guidelines are recommended for use on the basis of the AGREE-II quality assessment. Recommendations for the future development of clinical practice guidelines in migraine are provided. In particular, efforts should be made to ensure that guidelines are regularly updated and that guideline developers strive to locate and incorporate unpublished clinical trial evidence.

Abstract
Objectives: To perform an updated meta-analysis to evaluate the long-term cardiovascular and cerebrovascular outcomes among migraineurs.

Setting: A meta-analysis of cohort studies performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.

Data sources: The MEDLINE, Web of Science and Cochrane Central Register of Controlled Trials databases were searched for relevant articles.

Participants: A total of 16 cohort studies (18 study records) with 394 942 migraineurs and 757 465 non-migraineurs were analysed.

Primary and secondary outcome measures: Major adverse cardiovascular and cerebrovascular events (MACCE), stroke (ie, ischaemic, haemorrhagic or non-specified), myocardial infarction (MI) and all-cause mortality. The outcomes were reported at the longest available follow-up.

Data analysis: Summary-adjusted hazard ratios (HR) were calculated by random-effects Der-Simonian and Liard model. The risk of bias was assessed by the Newcastle-Ottawa Scale.

Results: Migraine was associated with a higher risk of MACCE (adjusted HR 1.42, 95% confidence interval [CI] 1.26 to 1.60, P<0.001, I2=40%) driven by a higher risk of stroke (adjusted HR 1.41, 95% CI 1.25 to 1.61, P<0.001, I2=72%) and MI (adjusted HR 1.23, 95% CI 1.03 to 1.43, P=0.006, I2=59%). There was no difference in the risk of all-cause mortality (adjusted HR 0.93, 95% CI 0.78 to 1.10, P=0.38, I2=91%), with a considerable degree of statistical heterogeneity between the studies. The presence of aura was an effect modifier for stroke (adjusted HR aura 1.56, 95% CI 1.30 to 1.87 vs adjusted HR no aura 1.11, 95% CI 0.94 to 1.31, P interaction=0.01) and all-cause mortality (adjusted HR aura 1.20, 95% CI 1.12 to 1.30 vs adjusted HR no aura 0.96, 95% CI 0.86 to 1.07, Pinteraction<0.001).

Conclusion: Migraine headache was associated with an increased long-term risk of cardiovascular and cerebrovascular events. This effect was due to an increased risk of stroke (both ischaemic and haemorrhagic) and MI. There was a moderate to severe degree of heterogeneity for the outcomes, which was partly explained by the presence of aura.

Prospero registration number: CRD42016052460.

Abstract
Purpose of review: Hemicrania Continua (HC) is a daily and persistent form of headache that is characterized by side-locked pain which is continuous, varies in severity and can be associated with conjunctival injection, lacrimation, nasal congestion, rhinorrhea, eyelid edema, forehead or facial sweating and miosis and/or ptosis.

Recent findings: Functional imaging studies have shown activation of subcortical structures such as the posterior hypothalamus and dorsal rostral pons, which are known to disinhibit the trigeminal autonomic reflex, a reflex responsible for autonomic outflow through trigeminal efferents. A similar pathway activation is seen in other Trigeminal autonomic cephalalgias (TAC) which solidifies HC as a TAC. While we also discuss promising treatments in our review, more evidence is needed before making them a standard of therapy for HC. This article aims to review the recent research on the diagnosis and clinical management of this potentially underdiagnosed primary headache disorder.

Abstract
Spontaneous intracranial hypotension typically results from spontaneous cerebrospinal fluid (CSF) leak, often at spine level and only rarely from skull base. Once considered rare, it is now diagnosed far more commonly than before and is recognized as an important cause of headaches. CSF leak leads to loss of CSF volume. Considering that the skull is a rigid noncollapsible container, loss of CSF volume is typically compensated by subdural fluid collections and by increase in intracranial venous blood which, in turn, causes pachymeningeal thickening, enlarged pituitary, and engorgement of cerebral venous sinuses on magnetic resonance imaging (MRI). Another consequence of CSF hypovolemia is sinking of the brain, with descent of the cerebellar tonsils and brainstem as well as crowding of the posterior fossa noted on head MRI. The clinical consequences of these changes include headaches that are often but not always orthostatic, nausea, occasional emesis, neck and interscapular pain, cochleovestibular manifestations, cranial nerve palsies, and several other manifestations attributed to pressure upon or stretching of the cranial nerves or brain or brainstem structures. CSF lymphocytic pleocytosis or increase in CSF protein concentration is not uncommon. CSF opening pressure is often low but can be within normal limits. Stigmata of disorders of connective tissue matrix are seen in some of the patients. An epidural blood patch, once or more, targeted or distant, at one site or bilevel, has emerged as the treatment of choice for those who have failed the conservative measures. Epidural injection of fibrin glue of both blood and fibrin glue can be considered in selected cases. Surgery to stop the leak is considered when the exact site of the leak has been determined by neurodiagnostic studies and when less invasive measures have failed. Subdural hematomas sometimes complicate the CSF leaks; a rebound intracranial hypertension after successful treatment of a leak is not rare. Cerebral venous sinus thrombosis as a complication is fortunately less common, and superficial siderosis and bibrachial amyotrophy are rare. Short-term recurrences are not uncommon, and long-term recurrences are not rare.

Abstract
Although pain after craniotomy is a clinically significant problem that has a continuously expanding literature, it is still a source of concern and controversy. Postcraniotomy headache (PCH) has been neglected for years. It is assessed regularly by only a few neurosurgical centers, and its frequency and severity tend to be underestimated by medical staff; hence, PCH is often undertreated and poorly managed. Various patient and surgical factors have an impact on the severity and incidence of PCH; thus, effective analgesic protocols are hard to define, which could explain the absence of available therapeutic guidelines. According to recent studies, certain surgical measures and the use of local anesthetics are promising in the prevention of PCH. NSAIDs seem to have inadequate analgesic effects, whereas opioids have a wide range of drawbacks; nevertheless, both types of medicaments are regarded as cornerstones of a balanced and adequate multimodal therapy. The purpose of this review is to collect the currently available knowledge about the incidence, assessment, pathophysiological mechanism, and predictors of acute and chronic PCH. Therefore, a broad search of the literature has been carried out to collect evidence of potential prevention and treatment strategies.

Abstract
Objective: Benzodiazepines (BZDs) are commonly used by chronic pain patients, despite limited evidence of any long-term benefits and concerns regarding adverse events and drug interactions, particularly in older patients. This article aims to: describe patterns of BZDs use; the demographic, physical, and mental health correlates of BZD use; and examine if negative health outcomes are associated with BZD use after controlling for confounders.

Subjects: A national sample of 1,220 chronic noncancer pain (CNCP) patients prescribed long-term opioids.

Methods: We report on baseline data from a prospective cohort study comparing four groups based on their current BZD use patterns. General demographics, pain, mental and physical comorbidity, and health service utilization were examined.

Results: One-third (N = 398, 33%) of participants reported BZD use in the past month, and 17% (N = 212) reported daily BZD use. BZD use was associated with: 1) greater pain severity, pain interference with life, and lower feelings of self-efficacy with respect to their pain; 2) being prescribed "higher-risk" (>200 mg oral morphine equivalent) doses of opioids; 3) using antidepressant and/or antipsychotic medications; 4) substance use (including more illicit and injection drug use, alcohol use disorder, and daily nicotine use); and 5) greater mental health comorbidity. After controlling for differences in demographic characteristics, physical and mental health, substance use, and opioid dose, BZD use was independently associated with greater past-month use of emergency health care such as ambulance or accident and emergency services.

Conclusions: CNCP patients using BZDs daily represent a high-risk group with multiple comorbid mental health conditions and higher rates of emergency health care use. The high prevalence of BZD use is inconsistent with guidelines for the management of CNCP or chronic mental health conditions.

Abstract
The classification of temporomandibular disorders (TMD) has progressed substantially over the past 25 years owing to the strategic implementation of an initial classification system based on core taxonomic principles. In this article, we describe the development of the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) and its translation into the multidimensional Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks-AAPT for chronic pain disorders. The initial scientific classification system (Research Diagnostic Criteria for Temporomandibular Disorders) relied on a boot-strapping process that did not attempt to solve all known clinical problems but, rather, focused on problems that could be solved at that time. The core design principles included using epidemiologic data, operationalized concepts, reliable methods, and the incorporation of the biopsychosocial model into a dual axis system. This system led to sufficient data collection internationally that the system itself could be revised, first by critical evaluation of all aspects, second by review from invited experts, and third by the construction of a revised taxonomy (DC/TMD) that maintained the core design principles of the Research Diagnostic Criteria for Temporomandibular Disorders. The resultant disorders with pain as a dominant feature exhibit substantial sensitivity and specificity, and they have been translated into the AAPT framework. The AAPT TMD criteria are part of an evidence-based classification system providing a systematic structure that includes 5 dimensions: diagnostic criteria, common features, comorbidities, consequences, and putative mechanisms. Future research will attempt to extend this AAPT domain from solely TMDs to include other orofacial pain conditions. PERSPECTIVE: The painful TMDs have well-established sensitivity and specificity, as based on the DC/TMD; their translation to the AAPT framework for chronic pain conditions provides a structure for consistent clinical application within the broader health care settings and for future research on the TMDs.

Abstract
There is a need to expand the current temporomandibular disorders' (TMDs) classification to include less common but clinically important disorders. The immediate aim was to develop a consensus-based classification system and associated diagnostic criteria that have clinical and research utility for less common TMDs. The long-term aim was to establish a foundation, vis-à-vis this classification system, that will stimulate data collection, validity testing and further criteria refinement. A working group [members of the International RDC/TMD Consortium Network of the International Association for Dental Research (IADR), members of the Orofacial Pain Special Interest Group (SIG) of the International Association for the Study of Pain (IASP), and members from other professional societies] reviewed disorders for inclusion based on clinical significance, the availability of plausible diagnostic criteria and the ability to operationalise and study the criteria. The disorders were derived from the literature when possible and based on expert opinion as necessary. The expanded TMDs taxonomy was presented for feedback at international meetings. Of 56 disorders considered, 37 were included in the expanded taxonomy and were placed into the following four categories: temporomandibular joint disorders, masticatory muscle disorders, headache disorders and disorders affecting associated structures. Those excluded were extremely uncommon, lacking operationalised diagnostic criteria, not clearly related to TMDs, or not sufficiently distinct from disorders already included within the taxonomy. The expanded TMDs taxonomy offers an integrated approach to clinical diagnosis and provides a framework for further research to operationalise and test the proposed taxonomy and diagnostic criteria.

Abstract
Objective: To identify predictors of prognosis and trial outcomes in prospective studies of people with chronic headache.

Methods: This was a systematic review of published literature in peer-reviewed journals. We included (1) randomized controlled trials (RCTs) of interventions for chronic headache that reported subgroup analyses and (2) prospective cohort studies, published in English, since 1980. Participants included adults with chronic headache (including chronic headache, chronic migraine, and chronic tension-type headache with or without medication overuse headache). We searched key databases using free text and MeSH terms. Two reviewers independently extracted data and assessed the methodologic quality of studies and overall quality of evidence identified using appropriate published checklists.

Results: We identified 16,556 titles, removed 663 duplicates, and reviewed 199 articles, of which 27 were included in the review-17 prospective cohorts and 10 RCTs with subgroup analyses reported. There was moderate-quality evidence indicating that depression, anxiety, poor sleep and stress, medication overuse, and poor self-efficacy for managing headaches are potential prognostic factors for poor prognosis and unfavorable outcomes from preventive treatment in chronic headache. There was inconclusive evidence about treatment expectations, age, age at onset, body mass index, employment, and several headache features.

Conclusions: This review identified several potential predictors of poor prognosis and worse outcome postinterventions in people with chronic headache. The majority of these are modifiable. The findings also highlight the need for more longitudinal high-quality research of prognostic factors in chronic headache.

Abstract
Migraine is a common brain disorder with high disability rates which involves a series of abnormal neuronal networks, interacting at different levels of the central and peripheral nervous system. An increase in the interest around migraine pathophysiology has allowed researchers to unravel certain neurophysiological mechanisms and neurotransmitter involvement culminating in the recent development of novel therapies, which might substantially change the clinical approach to migraine patients. The present review will highlight the current aspects of migraine pathophysiology, covering an understanding of the complex workings of the migraine state and the brain regions responsible for them. We will further discuss the therapeutic agents which have appeared in the most recent years for migraine care, from calcitonin gene-related peptide (CGRP) receptor antagonists, gepants; through serotonin 5-HT1F receptor agonists, ditans, and CGRP or CGRP receptor monoclonal antibodies to invasive and non-invasive neuromodulation techniques.

Abstract
Aims: The original Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) Axis I diagnostic algorithms have been demonstrated to be reliable. However, the Validation Project determined that the RDC/TMD Axis I validity was below the target sensitivity of ≥ 0.70 and specificity of ≥ 0.95. Consequently, these empirical results supported the development of revised RDC/TMD Axis I diagnostic algorithms that were subsequently demonstrated to be valid for the most common pain-related TMD and for one temporomandibular joint (TMJ) intra-articular disorder. The original RDC/TMD Axis II instruments were shown to be both reliable and valid. Working from these findings and revisions, two international consensus workshops were convened, from which recommendations were obtained for the finalization of new Axis I diagnostic algorithms and new Axis II instruments.

Methods: Through a series of workshops and symposia, a panel of clinical and basic science pain experts modified the revised RDC/TMD Axis I algorithms by using comprehensive searches of published TMD diagnostic literature followed by review and consensus via a formal structured process. The panel's recommendations for further revision of the Axis I diagnostic algorithms were assessed for validity by using the Validation Project's data set, and for reliability by using newly collected data from the ongoing TMJ Impact Project-the follow-up study to the Validation Project. New Axis II instruments were identified through a comprehensive search of the literature providing valid instruments that, relative to the RDC/TMD, are shorter in length, are available in the public domain, and currently are being used in medical settings.

Results: The newly recommended Diagnostic Criteria for TMD (DC/TMD) Axis I protocol includes both a valid screener for detecting any pain-related TMD as well as valid diagnostic criteria for differentiating the most common pain-related TMD (sensitivity ≥ 0.86, specificity ≥ 0.98) and for one intra-articular disorder (sensitivity of 0.80 and specificity of 0.97). Diagnostic criteria for other common intra-articular disorders lack adequate validity for clinical diagnoses but can be used for screening purposes. Inter-examiner reliability for the clinical assessment associated with the validated DC/TMD criteria for pain-related TMD is excellent (kappa ≥ 0.85). Finally, a comprehensive classification system that includes both the common and less common TMD is also presented. The Axis II protocol retains selected original RDC/TMD screening instruments augmented with new instruments to assess jaw function as well as behavioral and additional psychosocial factors. The Axis II protocol is divided into screening and comprehensive self report instrument sets. The screening instruments' 41 questions assess pain intensity, pain-related disability, psychological distress, jaw functional limitations, and parafunctional behaviors, and a pain drawing is used to assess locations of pain. The comprehensive instruments, composed of 81 questions, assess in further detail jaw functional limitations and psychological distress as well as additional constructs of anxiety and presence of comorbid pain conditions.

Conclusion: The recommended evidence-based new DC/TMD protocol is appropriate for use in both clinical and research settings. More comprehensive instruments augment short and simple screening instruments for Axis I and Axis II. These validated instruments allow for identification of patients with a range of simple to complex TMD presentations.

Abstract
Background: Migraine is a complex neurovascular disorder with a strong genetic component. There are rare monogenic forms of migraine, as well as more common polygenic forms; research into the genes involved in both types has provided insights into the many contributing genetic factors. This review summarises advances that have been made in the knowledge and understanding of the genes and genetic variations implicated in migraine etiology.

Findings: Migraine is characterised into two main types, migraine without aura (MO) and migraine with aura (MA). Hemiplegic migraine is a rare monogenic MA subtype caused by mutations in three main genes - CACNA1A, ATP1A2 and SCN1A - which encode ion channel and transport proteins. Functional studies in cellular and animal models show that, in general, mutations result in impaired glutamatergic neurotransmission and cortical hyperexcitability, which make the brain more susceptible to cortical spreading depression, a phenomenon thought to coincide with aura symptoms. Variants in other genes encoding ion channels and solute carriers, or with roles in regulating neurotransmitters at neuronal synapses, or in vascular function, can also cause monogenic migraine, hemiplegic migraine and related disorders with overlapping symptoms. Next-generation sequencing will accelerate the finding of new potentially causal variants and genes, with high-throughput bioinformatics analysis methods and functional analysis pipelines important in prioritising, confirming and understanding the mechanisms of disease-causing variants. With respect to common migraine forms, large genome-wide association studies (GWAS) have greatly expanded our knowledge of the genes involved, emphasizing the role of both neuronal and vascular pathways. Dissecting the genetic architecture of migraine leads to greater understanding of what underpins relationships between subtypes and comorbid disorders, and may have utility in diagnosis or tailoring treatments. Further work is required to identify causal polymorphisms and the mechanism of their effect, and studies of gene expression and epigenetic factors will help bridge the genetics with migraine pathophysiology.

Conclusions: The complexity of migraine disorders is mirrored by their genetic complexity. A comprehensive knowledge of the genetic factors underpinning migraine will lead to improved understanding of molecular mechanisms and pathogenesis, to enable better diagnosis and treatments for migraine sufferers.

Abstract
All patients with migraine merit acute treatment, which should optimally achieve a sustained pain-free response. Maximum acute treatment is associated with reduced risk of transformation of episodic to chronic migraine. The American Headache Society published the most recent complete evidence assessment of acute migraine treatments in 2015. Noninvasive neuromodulation represents a new, Food and Drug Administration-approved nonsignificant risk alternative for acute migraine therapy. The future of acute migraine treatment includes new devices and formulations of existing medications, new classes of acute medications, and new noninvasive nonsignificant risk neuromodulation devices, with many anticipated in the next few years.

Abstract
Migraine and tension-type headaches (TTHs) comprise a significant burden of neurological disease globally. Trochleodynia, also known as primary trochlear headache or trochleitis, may go unrecognized and contribute to worsening of these headache disorders. It may also present in isolation. We review the English literature on this under-recognized condition and describe what is known about the theorized pathophysiology, clinical presentation, and differential diagnosis. We also present a management algorithm for patients presenting with trochleodynia.

This discussion paper aims to inform proceedings at the World Conference on Social Determinants of Health [‎Rio de Janeiro, Brazil 19-21 October, 2011]‎