Cannabis, pain, and sleep: lessons from therapeutic clinical trials of Sativex, a cannabis-based medicine

Cannabis sativa L. has been utilized for treatment of pain and sleep disorders since ancient times. This review examines modern studies on effects of Delta9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on sleep. It goes on to report new information on the effects on sleep in the context of medical treatment of neuropathic pain and symptoms of multiple sclerosis, employing standardized oromucosal cannabis-based medicines containing primarily THC, CBD, or a 1 : 1 combination of the two (Sativex). Sleep-laboratory results indicate a mild activating effect of CBD, and slight residual sedation with THC-predominant extracts. Experience to date with Sativex in numerous Phase I-III studies in 2000 subjects with 1000 patient years of exposure demonstrate marked improvement in subjective sleep parameters in patients with a wide variety of pain conditions including multiple sclerosis, peripheral neuropathic pain, intractable cancer pain, and rheumatoid arthritis, with an acceptable adverse event profile. No tolerance to the benefit of Sativex on pain or sleep, nor need for dosage increases have been noted in safety extension studies of up to four years, wherein 40-50% of subjects attained good or very good sleep quality, a key source of disability in chronic pain syndromes that may contribute to patients' quality of life.     

Sleep in the surgical intensive care unit: continuous polygraphic recording of sleep in nine patients receiving postoperative care.

Sleep was studied in nine patients for two to four days after major non-cardiac surgery by continuous polygraphic recording of electroencephalogram, electrooculogram, and electromyogram. Presumed optimal conditions for sleep were provided by a concerted effort by staff to offer constant pain relief and reduce environmental disturbance to a minimum. All patients were severely deprived of sleep compared with normal. The mean cumulative sleep time (stage 1 excluded) for the first two nights, daytime sleep included, was less than two hours a night. Stages 3 and 4 and rapid eye movement sleep were severely or completely suppressed. The sustained wakefulness could be attributed to pain and environmental disturbance to only minor degree. Sleep time as estimated by nursing staff was often grossly misjudged and consistently overestimated when compared with the parallel polygraphic recording. The grossly abnormal sleep pattern observed in these patients may suggest some fundamental disarrangement of the sleep-wake regulating mechanism.     

Knee Pain and Low Back Pain Additively Disturb Sleep in the General Population: A Cross-Sectional Analysis of the Nagahama Study

Introduction

Association of knee and low back pain with sleep disturbance is poorly understood. We aimed to clarify the independent and combined effects of these orthopedic symptoms on sleep in a large-scale general population.

Methods

Cross-sectional data about sleep and knee/low back pain were collected for 9,611 community residents (53±14 years old) by a structured questionnaire. Sleep duration less than 6 h/d was defined as short sleep. Sleep quality and the presence of knee and low back pain were evaluated by dichotomous questions. Subjects who complained about knee or low back pains were graded by tertiles of a numerical response scale (NRS) score and a Roland-Morris disability questionnaire (RDQ) score respectively. Multivariate regression analyses were performed to determine the correlates of short sleep duration and poor sleep quality.

Results

Frequency of participants who complained of the orthopedic symptoms was as follows; knee pain, 29.0%; low back pain, 42.0% and both knee and low back pain 17.6%. Both knee and low back pain were significantly and independently associated with short sleep duration (knee pain: odds ratio (OR) = 1.19, p<0.01; low back pain: OR = 1.13, p = 0.01) and poor sleep quality (knee pain: OR = 1.22, p<0.01; low back pain; OR = 1.57, p<0.01). The group in the highest tertile of the NRS or RDQ score had the highest risk for short sleep duration and poor sleep quality except for the relationship between the highest tertile of the RDQ score and short sleep duration.(the highest tertile of the NRS: OR for short sleep duration = 1.31, p<0.01; OR for poor sleep quality = 1.47, p<0.01; the highest tertile of the RDQ: OR for short sleep duration = 1.11, p = 0.12; OR for poor sleep quality = 1.81, p<0.01) Further, coincident knee and low back pain raised the odds ratios for short sleep duration (either of knee or low back pain: OR = 1.10, p = 0.06; both knee and low back pain: OR = 1.40, p<0.01) and poor sleep quality (either of knee or low back pain: OR = 1.61, p<0.01; both knee and low back pain: OR = 2.17, p<0.01).

Conclusion

Knee and low back pains were independently associated with short sleep duration and poor sleep quality. Further, they additively increased the correlation with these sleep problems in the general population.     

Spectrum of rapid eye movement sleep behavior disorder (overlap between rapid eye movement sleep behavior disorder and other parasomnias)

Parasomnia Overlap Disorder (POD) was described and named in 1997 with a series of 33 cases of rapid eye movement (REM) sleep behavior disorder (RBD) combined with a disorder of arousal from non-rapid eye movement (NREM) sleep (sleepwalking, sleep terrors) that emerged idiopathically or symptomatically with neurological and other disorders. POD is a subtype of RBD in the International Classification of Sleep Disorders Diagnostic and Coding Manual, second edition (ICSD-2). An updated classification of POD also includes subclinical RBD-NREM parasomnia, RBD-sleep-related eating disorder, RBD-sexsomnia, RBD-rhythmic movement disorder, and status dissociatus (SD), which is another subtype of RBD in the ICSD-2. Similar to POD, a core feature of SD is sleep motor-behavioral dyscontrol, with release of dream-related behaviors suggestive of RBD, but with nearly continuous ambiguous polygraphic sleep precluding the identification of NREM/REM sleep states. SD exemplifies extreme state dissociation. SD is always a symptomatic disorder, and is causally associated with a broad range of neurologic disorders, often with thalamic, limbic, striatal, and pontine involvement. The parasomnia behaviors associated with POD and SD — typical RBD behaviors — can often be controlled with bedtime clonazepam therapy, including the abnormal dreaming.

     

Selective REM Sleep Deprivation Improves Expectation-Related Placebo Analgesia

The placebo effect is a neurobiological and psychophysiological process known to influence perceived pain relief. Optimization of placebo analgesia may contribute to the clinical efficacy and effectiveness of medication for acute and chronic pain management. We know that the placebo effect operates through two main mechanisms, expectations and learning, which is also influenced by sleep. Moreover, a recent study suggested that rapid eye movement (REM) sleep is associated with modulation of expectation-mediated placebo analgesia. We examined placebo analgesia following pharmacological REM sleep deprivation and we tested the hypothesis that relief expectations and placebo analgesia would be improved by experimental REM sleep deprivation in healthy volunteers. Following an adaptive night in a sleep laboratory, 26 healthy volunteers underwent classical experimental placebo analgesic conditioning in the evening combined with pharmacological REM sleep deprivation (clonidine: 13 volunteers or inert control pill: 13 volunteers). Medication was administered in a double-blind manner at bedtime, and placebo analgesia was tested in the morning. Results revealed that 1) placebo analgesia improved with REM sleep deprivation; 2) pain relief expectations did not differ between REM sleep deprivation and control groups; and 3) REM sleep moderated the relationship between pain relief expectations and placebo analgesia. These results support the putative role of REM sleep in modulating placebo analgesia. The mechanisms involved in these improvements in placebo analgesia and pain relief following selective REM sleep deprivation should be further investigated.     

Effect of hyoscine butylbromide and atropine on heart rate during nocturnal sleep

This is a single blind crossover study designed to test the effects of hyoscine butylbromide (HBB), an anticholinergic which does not cross the blood brain barrier (BBB), on the temporal changes in heart rate during nocturnal sleep. The effects were compared with atropine sulphate which is known to cross the BBB. Ten healthy male volunteers slept in the JIPMER sleep disorders laboratory for three nights and received either saline, atropine sulphate (0.4 mg, i.v.) or HBB (10 mg, i.v.) just prior to sleep onset. All night polysomnography recording was done to monitor heart rate during the specific stages of sleep. The normal physiological fall in heart rate is blunted by both drugs during slow wave sleep whereas only HBB prevented the fall in rapid eye movement sleep. Therefore, HBB may be a better choice as pre-anaesthetic medication for patients with cardiac abnormalities since it does not alter heart rate during both slow wave sleep and rapid eye movement sleep.     

Polysomnographic Assessment of Sleep Comorbidities in Drug-Na?ve Narcolepsy-Spectrum Disorders—A Japanese Cross-Sectional Study

This is a large cross-sectional study which aimed to investigate comorbidity rate, degree of sleep-related breathing disorder, polysomnigraphically diagnosible rapid eye movement sleep behavior disorder/rapid eye movement sleep without atonia and periodic limb movements during sleep in Japanese drug-naïve patients with narcolepsy-spectrum disorders. A total of 158 consecutive drug naïve patients with narcolepsy with cataplexy, 295 patients with narcolepsy without cataplexy and 395 patients with idiopathic hypersomnia without long sleep time were enrolled. From retrospectively analyzed data of nocturnal polysomnography and multiple sleep latency test, higher rates of periodic limb movements during sleep (> = 15 h^-1) (10.2%) and polysomnographically diagnosable rapid eye movement sleep behavior disorder (1.9%) were found in patients with narcolepsy with cataplexy. They had more severe periodic limb movements during sleep especially during rapid eye movement sleep and higher percentages of rapid eye movement sleep without atonia than the other two patient groups. In the present large sample study, Japanese drug naïve patients with narcolepsy with cataplexy showed the highest comorbidity rates of periodic limb movements during sleep, polysomnographically diagnosable rapid eye movement sleep behavior disorder and rapid eye movement sleep without atonia among those with the other narcolepsy-spectrum disorders; the rates were lower than those for Western patients.     

Movement disorders in sleep: Parkinson's disease and restless legs syndrome.

In recent years, sleep abnormalities have increasingly been observed in patients with movement disorders. During sleep, most patients with Parkinson's disease also exhibit the movements characteristically seen during the wake period. Movement activity during sleep may impair sleep quality and lead to daytime sleepiness and reduced quality of life. Disordered REM sleep with enhanced muscle tone is common in patients with neurodegenerative disease, and may precede the clinically evident symptoms of Parkinson's disease by years. Sleep disorders in patients with Parkinson's disease are common, and require the application of individual treatment strategies. A further frequent disorder primarily classified as a sleep disorder (dyssomnia) is the restless legs syndrome (RLS), which is closely related to the nocturnal periodic limb movement disorder and affects up to 15% of the population. The present review focuses on nocturnal motor activity and sleep in Parkinson's disease and RLS.     

孤独症儿童生存质量、睡眠质量现状调查及睡眠障碍的影响因素分析

摘要 目的：分析孤独症儿童生存质量、睡眠质量现状,探讨其睡眠障碍的影响因素。方法：选择2017年1月至2019年12月期间我院收治的孤独症儿童100例作为研究组,另选同期于我院进行体检的健康儿童100例作为对照组,分别应用生存质量简易量表、社会支持评定量表、儿童睡眠质量调查问卷调查两组生存质量、社会支持情况、睡眠质量。应用单因素及多因素Logistic回归分析孤独症儿童睡眠障碍的影响因素。结果：研究组儿童生存质量简易量表的主观标准评分、客观标准评分及社会支持评定量表的主观支持评分、客观支持评分、对社会支持的利用度评分、总分均显著低于对照组（P＜0.05）。研究组入睡困难、睡眠不安、间断睡眠、夜惊、夜间尿床、打鼾、梦呓、梦游、张口呼吸、夜间磨牙、睡眠出汗发生率均显著高于对照组（P＜0.05）,两组梦魇发生率比较无统计学差异（P>0.05）。研究组患儿中存在睡眠障碍的46例,无睡眠障碍的54例。单因素分析显示,睡眠障碍组父母关系差、家族精神病史、新生儿窒息史、出生体重<2500 g比例显著高于无睡眠障碍组（P＜0.05）。多因素Logistic回归分析显示,父母关系差、有家族精神疾病史、有新生儿期窒息史、出生体重<2500 g是孤独症儿童睡眠障碍的危险因素（P＜0.05）。结论：与健康儿童相比,孤独症儿童生存质量、社会支持情况较差,睡眠障碍发生率也较高,父母关系差、有家族精神疾病史、有新生儿期窒息史、出生体重<2500 g是孤独症儿童睡眠障碍的危险因素。     

Sleep Complaints and Polysomnographic Findings: A Study of Nuclear Power Plant Shift Workers

The literature widely recognizes that shift workers have more health complaints than the general population. The objective of this study was to describe the prevalence of sleep complaints and verify the polysomnographic (PSG) variables of shift workers in two Brazilian nuclear power plants. We carried out a subjective evaluation with a sleep questionnaire. Based on these results, the interviewees that reported sleep‐related complaints were referred for polysomnographic evaluation. Of the 327 volunteers initially evaluated by the sleep questionnaire, 113 (35%) reported sleep complaints; they were significantly older, had higher body mass index (BMI), and worked more years on shifts than those without sleep complaints. Of these 113, 90 met criteria for various sleep disorders: 30 (9%) showed obstructive sleep apnea (OSA), 18 (5.5%) showed limb movement, and 42 (13%) evidenced both sleep problems and had a significantly higher proportion of sleep stage 1 and arousals compared with the 23 shift workers that had no indices of sleep problems. The present study found that 90 (27.5%) of the evaluated participants met the PSG criteria of some type of clinical sleep disorder. This high proportion should be investigated for associations with other aspects of work, such as working hours, working schedule, years performing shift work, and access to health services. Due to the strong association between sleep disorders and the incidence of fatigue and sleepiness, the evaluation of the sleep patterns and complaints of shift workers is essential and should be considered to be one of the basic strategies of industry to prevent accidents.     

Diagnosis of sleep disorders and medical sleep-related diseases--a review]

A person's well-being and health are greatly affected by disorders of sleep and wakefulness. It is of the utmost importance to diagnose and treat such conditions, since the associated daytime sleepiness is a major risk factor for accidents. Early establishment of the correct diagnosis paves the way to achieving an excellent therapeutic outcome. Health-economic requirements of appropriateness and necessity mandate the specific use of cost- and time-intensive examinations in the sleep laboratory. In accordance with the guidelines for "non-restorative sleep", severe and chronic sleep disorders can be diagnosed outside the sleep lab if the underlying cause can already be identified on the basis of the patient's history. Such is usually the case in sleep disorders caused by external influences, disturbed circadian rhythm or pre-existing neurological, psychiatric or internal disorders. Standardized questionnaires are used to record and evaluate the patient's complaints, and vigilance testing to assess impaired sustained attention during the day. Excessive daytime sleepiness is quantified by the multiple sleep latency test (MSLT). In the case of some disorders such as apnoea, or periodic leg movements, simplified ambulatory methods have been developed to enable their detection at an early stage. The gold standard for the diagnosis of sleep disorders in the sleep lab is cardiorespiratory polysomnography. The relevant biosignals for the assessment of sleep, respiration, heart function, the cardiovascular system and movement are well established. Some of the sensors employed need further improvement. Numerous methods for signal analysis are still undergoing development, and currently available automatic evaluation systems are not yet reliable enough to obviate the need for manual interpretation.     

An In Vitro Adult Mouse Muscle-nerve Preparation for Studying the Firing Properties of Muscle Afferents

Muscle sensory neurons innervating muscle spindles and Golgi tendon organs encode length and force changes essential to proprioception. Additional afferent fibers monitor other characteristics of the muscle environment, including metabolite buildup, temperature, and nociceptive stimuli. Overall, abnormal activation of sensory neurons can lead to movement disorders or chronic pain syndromes. We describe the isolation of the extensor digitorum longus (EDL) muscle and nerve for in vitro study of stretch-evoked afferent responses in the adult mouse. Sensory activity is recorded from the nerve with a suction electrode and individual afferents can be analyzed using spike sorting software. In vitro preparations allow for well controlled studies on sensory afferents without the potential confounds of anesthesia or altered muscle perfusion. Here we describe a protocol to identify and test the response of muscle spindle afferents to stretch. Importantly, this preparation also supports the study of other subtypes of muscle afferents, response properties following drug application and the incorporation of powerful genetic approaches and disease models in mice.     

Sleep complaints and polysomnographic findings: a study of nuclear power plant shift workers

The literature widely recognizes that shift workers have more health complaints than the general population. The objective of this study was to describe the prevalence of sleep complaints and verify the polysomnographic (PSG) variables of shift workers in two Brazilian nuclear power plants. We carried out a subjective evaluation with a sleep questionnaire. Based on these results, the interviewees that reported sleep-related complaints were referred for polysomnographic evaluation. Of the 327 volunteers initially evaluated by the sleep questionnaire, 113 (35%) reported sleep complaints; they were significantly older, had higher body mass index (BMI), and worked more years on shifts than those without sleep complaints. Of these 113, 90 met criteria for various sleep disorders: 30 (9%) showed obstructive sleep apnea (OSA), 18 (5.5%) showed limb movement, and 42 (13%) evidenced both sleep problems and had a significantly higher proportion of sleep stage 1 and arousals compared with the 23 shift workers that had no indices of sleep problems. The present study found that 90 (27.5%) of the evaluated participants met the PSG criteria of some type of clinical sleep disorder. This high proportion should be investigated for associations with other aspects of work, such as working hours, working schedule, years performing shift work, and access to health services. Due to the strong association between sleep disorders and the incidence of fatigue and sleepiness, the evaluation of the sleep patterns and complaints of shift workers is essential and should be considered to be one of the basic strategies of industry to prevent accidents.     

Exploring How Pain Leads to Productivity Loss in Primary Care Consulters for Osteoarthritis: A Prospective Cohort Study

Objective

Osteoarthritis pain has become a leading cause of decreased productivity and work disability in older workers, a major concern in primary care. How osteoarthritis pain leads to decreased productivity at work is unclear; the aim of this study was to elucidate causal mechanisms and thus identify potential opportunities for intervention.

Methods

Population-based prospective cohort study of primary care consulters with osteoarthritis. Path analysis was used to test proposed mechanisms by examining the association between pain at baseline, and onset of work productivity loss at three years for mediation by physical limitation, depression, poor sleep and poor coping mechanisms.

Results

High pain intensity was associated with onset of work productivity loss (Adjusted Odds Ratio 2.5; 95%CI 1.3, 4.8). About half of the effect of pain on work productivity was a direct effect, and half was mediated by the impact of pain on physical function. Depression, poor sleep quality and poor coping did not mediate the association between high pain intensity and onset of work productivity loss.

Conclusions

As pain is a major cause of work productivity loss, results suggest that decreasing pain should be a major focus. However, successfully improving function may have an indirect effect by decreasing the impact of pain on work productivity, especially important as significant pain reduction is often difficult to achieve. Although depression, sleep problems, and coping strategies may be directly related to work productivity loss, addressing these issues may not have much effect on the significant impact of pain on work productivity.     

Continuous non-invasive blood pressure monitoring in patients with sleep disorders.

Sleep related breathing disorders are of high prevalence and are often associated with essential hypertension. It is therefore necessary to study blood pressure continuously in all patients with sleep related breathing disorders and arterial hypertension as well as in all patients with essential hypertension and suspected sleep apnoea. To investigate the usefulness of a non-invasive continuous volume-clamp method during sleep we used this technique in parallel with 130 sleep recordings and performed a validation study of the Finapres instrument on a subgroup where continuous invasive blood pressure recordings were available. Absolute pressure values of Finapres are valid when the position and the movement of the sensor were carefully observed and only appropriate segments of the recordings were taken for further evaluation. The high beat to beat resolution of the systolic and diastolic pressure is the main advantage of this non-invasive technique because it reflects rapid blood pressure variations as they occur in sleep related breathing disorders. This could be investigated only invasively until now.     

A hip abduction exercise prior to prolonged standing increased movement while reducing cocontraction and low back pain perception in those initially reporting low back pain

Persons who develop low back pain from prolonged standing exhibit increased muscle cocontraction, decreased movement and increased spine extension. However, it is unclear how these factors relate to pain development. The purpose of this study was to use hip abductor fatigue to manipulate muscle activity patterns and determine its effects on standing behaviours and pain development. Forty participants stood for two hours twice, once following a hip abductor fatigue exercise (fatigue), and once without exercise beforehand (control). Trunk and gluteal muscle activity were measured to determine cocontraction. Lumbo-pelvic angles and force plates were used to assess posture and movement strategies. Visual analog scales differentiated pain (PDs) and non-pain developers (NPDs). PDs reported less low back pain during the fatigue session, with females having earlier reductions of similar scale than males. The fatigue session reduced gluteal and trunk cocontraction and increased centre of pressure movement; male and female PDs had opposing spine posture compensations. Muscle fatigue prior to standing reduced cocontraction, increased movement during standing and reduced the low back pain developed by PDs; the timing of pain reductions depended on spine postures adopted during standing.     

Sleepwalking,night terrors,and consciousness.

OBJECTIVE--To determine some personality and psychoneurotic characteristics of adults who have the sleepwalking-night terrors syndrome. DESIGN--Prospective assessment of two groups of consecutive patients with a firm diagnosis of either of two specific sleep disorders as established clinically and by polysomnography. SETTING--Outpatient sleep disorders clinic and sleep laboratory in a tertiary referral centre. PATIENTS--12 Patients referred consecutively to the clinic in whom a diagnosis of sleepwalking (six) or night terrors (six) was confirmed. MAIN OUTCOME MEASURES--Psychological characteristics as measured at the time of clinical assessment by means of the Eysenck personality questionnaire, the hostility and direction of hostility questionnaire, and the Crown-Crisp experiential index. RESULTS--Both groups scored exceptionally highly on the hysteria scale of the Crown-Crisp experiential index and the night terrors group also scored highly on the anxiety scale. The patients with sleepwalking also scored highly on a measure of externally directed hostility. CONCLUSIONS--The physiological and psychological features identified in these patients, possibly reflecting different expressions of a constitutional cerebral characteristic, may be explored in terms of hysterical dissociation. The findings contribute to the debate concerning the nature of sleepwalking, in particular with and without the forensic aspects.     

The temporal development of fatty infiltrates in the neck muscles following whiplash injury: an association with pain and posttraumatic stress

BACKGROUND: Radiological findings associated with poor recovery following whiplash injury remain elusive. Muscle fatty infiltrates (MFI) in the cervical extensors on magnetic resonance imaging (MRI) in patients with chronic pain have been observed. Their association with specific aspects of pain and psychological factors have yet to be explored longitudinally. MATERIALS AND FINDINGS: 44 subjects with whiplash injury were enrolled at 4 weeks post-injury and classified at 6 months using scores on the Neck Disability Index as recovered, mild and moderate/severe. A measure for MFI and patient self-report of pain, loss of cervical range of movement and posttraumatic stress disorder (PTSD) were collected at 4 weeks, 3 months and 6 months post-injury. The effects of time and group and the interaction of time by group on MFI were determined. We assessed the mediating effect of posttraumatic stress and cervical range of movement on the longitudinal relationship between initial pain intensity and MFI. There was no difference in MFI across all groups at enrollment. MFI values increased in the moderate/severe group and were significantly higher in comparison to the recovered and mild groups at 3 and 6 months. No differences in MFI values were found between the mild and recovered groups. Initial severity of PTSD symptoms mediated the relationship between pain intensity and MFI at 6 months. Initial ROM loss did not. CONCLUSIONS: MFI in the cervical extensors occur soon following whiplash injury and suggest the possibility for the occurrence of a more severe injury with subsequent PTSD in patients with persistent symptoms.     

Timing and consolidation of human sleep, wakefulness, and performance by a symphony of oscillators

Daily rhythms in sleep and waking performance are generated by the interplay of multiple external and internal oscillators. These include the light-dark and social cycles, a circadian hypothalamic oscillator oscillating virtually independently of behavior, and a homeostatic oscillator driven primarily by sleep-wake behavior. Both internal oscillators contribute to variation in many aspects of sleep and wakefulness (e.g., sleep timing and duration, REM sleep, non-REM sleep, REM density, sleep spindles, slow-wave sleep, electroencephalographic oscillations during wakefulness and sleep, and performance parameters, including attention and memory). The relative contribution of the oscillators varies greatly between these variables. Sleep and performance cannot be predicted by either oscillator independently but critically depend on their phase relationship and amplitude. The homeostatic oscillator feeds back onto the central pacemaker or its outputs. Thus, the amplitude of observed circadian variation in sleep and performance depends on how long we have been asleep or awake. During entrainment to external 24-h cycles, the opposing interplay between circadian and homeostatic changes in sleep propensity consolidates sleep and wakefulness. Some physiological correlates and mediators of both the circadian process (e.g., melatonin and hypocretin rhythms) and the homeostat (e.g., EEG, slow-wave activity, and adenosine release) have been established, offering targets for the development of countermeasures for circadian sleep and performance disorders. Interindividual differences in sleep timing, duration, and morning or evening preference are associated with changes of circadian or sleep homeostatic processes or both. Molecular genetic correlates, including polymorphisms in clock genes, of some of these interindividual differences are emerging.     

Mechanisms of pain arising from articular tissues

This paper reviews the peripheral and central neural mechanisms underlying pain from articular tissues innervated by spinal and trigeminal afferents. The paper especially addresses trigeminal mechanisms related to pain from the temporomandibular joint and its associated craniofacial musculature. Recent studies have shown the existence of articular nociceptive primary afferents that project to the spinal cord dorsal horn and trigeminal brainstem complex. A particular feature of most neurones receiving these deep nociceptive afferent inputs is their responsivity also to cutaneous nociceptive afferent inputs. This suggests the involvement of these neurones not only in the detection of acute articular pain, but also in the hyperalgesia and poor localization, spread, and referral of pain that characterize many painful conditions of joints and other deep structures. While only limited information is available on related higher brain centre mechanisms, convergence and interaction between cutaneous and deep afferent inputs also seem to be a characteristic of somatosensory neurones in the thalamus and somatosensory cerebral cortex. Muscle and autonomic reflexes may be induced by such deep noxious stimuli, but the functional significance of some of these effects (e.g., in relation to clinical concepts of myofascial dysfunction) requires further study in more appropriate functional settings.