Mar

In recent years, increasing attention has focused on the treatment of chronic pain with a considerable number of research and publications about it.  At the same time, opioid prescription, use, abuse and death related to the inappropriate use of opioids have significantly increased over the last 10 years.  Some reports indicated that there were more than 100 ‘pain clinics’ within a one-mile radius in South Florida, between 2009 and 2010, which led to the birth of new opioid prescription laws in Florida and many other states to restrict the use of opioids.  In the face of clinical and social turmoil related to opioid use and abuse, a fundamental question facing each clinician is: are opioids effective and necessary for chronic non-malignant pain?

Chronic low back pain (LBP) is the most common pain condition in pain clinics and most family physician offices, which ‘requires’ chronic use of opioids.  Nampiaparampil et al conducted a literature review in 2012¹ and found only one high-quality study on oral opioid therapy for LBP, which showed significant efficacy in pain relief and patient function. Current consensus believes that there is weak evidence demonstrating favourable effectiveness of opioids compared to placebo in chronic LBP.²Opioids may be considered in the treatment of chronic LBP if a patient fails other treatment modalities such as non-steroidal anti-inflammatory drugs (NSAIDs), antidepressants, physical therapy or steroid injections. Opioids should be avoided if possible, especially in adolescents who are at high risk of opioid overdose, misuse, and addiction.  It has been demonstrated that the majority of the population with degenerative disc disease, including a disc herniation have no back pain.  A Magnetic Resonance Imaging (MRI) report or film with a disc herniation should not be an automatic ‘passport’ for access to narcotics.

Failed back surgery syndrome (FBSS) is often refractory to most treatment modalities and sometimes very debilitating. There are no well-controlled clinical studies to approve or disapprove the use of opioids in FBSS.  Clinical experience suggests oral opioids may be beneficial and necessary to many patients suffering from severe back pain due to FBSS. Intraspinal opioids delivered via implanted pumps may be indicated in those individuals who cannot tolerate oral medications.   For elderly patients with severe pain due to spinal stenosis, there is no clinical study to approve or disprove the use of opioids. However, due to the fact that NSAIDs may cause serious side effects in gastrointestinal, hepatic and renal systems, opioid therapy may still be a choice in carefully selected patients.

Most studies for pharmacological treatment of neuropathic pain are conducted with diabetic peripheral neuropathy (DPN) patients. Several randomized clinical controlled studies have demonstrated evidence that some opioids, such as morphine sulphate, tramadol,³ and oxycodone controlled-release,⁴ are probably effective in reducing pain and should be considered as a treatment of choice (Level B evidence), even though anti-epileptics such as pregabalin should still be used as the first line medication.⁵

Some studies indicate opioids may be superior to placebo in relieving pain due to acute migraine attacks and Fiorinal with codeine may be effective for tension headache.  However there is lack of clinical evidence supporting long-term use of opioids for chronic headaches such as migraine, chronic daily headache, medication overuse headache, or cervicogenic headache.  Currently there are large amounts of opioids being prescribed for headaches because of patients' demands.  Neuroscience data on the effects of opioids on the brain has raised serious concerns for long-term safety and has provided the basis for the mechanism by which chronic opioid use may induce progression of headache frequency and severity.⁶ A recent study found chronic opioid use for migraine associated with more severe headache-related disability, symptomology, comorbidities (depression, anxiety, and cardiovascular disease and events), and greater healthcare resource utilization.⁷

Many patients with fibromyalgia (FM) come into pain clinics to ask for, or even demand, prescriptions for opioids. There is insufficient evidence to support the routine use of opioids in fibromyalgia.⁸ Recent studies have suggested that central sensitization may play for role in the aetiology of FM. Three central nervous system (CNS) agents (pregabalin, duloxetine and milnacipran) have been approved by United States Food and Drug Administration (US FDA) for treatment of FM.  However, opioids are still commonly prescribed by many physicians for FM patients by ‘tradition’, sometimes even with the combination of a benzodiazapine and muscles relaxant - Soma. We have observed negative health and psychosocial status in patients using opioids and labeled with FM. Opioids should be avoided whenever possible in FM patients in face of widespread abuse and lack of clinical evidence.⁹

Adolescents with mild non-malignant chronic pain rarely require long-term opioid therapy.¹⁰ Opioids should be avoided if possible in adolescents, who are at high risk of opioid overdose, misuse, and addiction.  Patients with adolescents living at home should store their opioid medication safely.

In conclusion, opioids are effective and necessary in certain cases. However, currently no single drug stands out as the best therapy for managing chronic non-malignant pain, and current opioid treatment is not sufficiently evidence-based.  More well-designed clinical studies are needed to confirm the clinical efficacy and necessity for using opioids in the treatment of chronic non-malignant pain. Before more evidence becomes available, and in the face of widespread abuse of opioids in society and possible serious behavioural consequences to individual patients, a careful history and physical examination, assessment of aberrant behavior, controlled substance agreement, routine urine drug tests, checking of state drug monitoring system (if available), trials of other treatment modalities, and continuous monitoring of opioid compliance should be the prerequisites before any opioids are prescribed. 

Opioid prescriptions should be given as indicated, not as ‘demanded’.

Introduction

Nosocomial pneumonia in patients receiving mechanical ventilation, also called ventilator-associated pneumonia (VAP), is an important nosocomial infection worldwide which leads to an increased length of hospital stay, healthcare costs, and mortality.^(1,2,3,4,5) The incidence of VAP ranges from 9% to 27% with a crude mortality rate that can exceed up to 50%.  ^(6,7,8,9) Aspiration of bacteria from the upper digestive tract is an important proposed mechanism in the pathogenesis of VAP.^{(9, 10)}  The normal flora of the oral cavity may include up to 350 different bacterial species, with tendencies for groups of bacteria to colonize different surfaces in the mouth. For example, Streptococcus mutans, Streptococcus sanguis, Actinomyces viscosus, and Bacteroides gingivalis mainly colonize the teeth; Streptococcus salivarius mainly colonizes the dorsal aspect of the tongue; and Streptococcus mitis is found on both buccal and tooth surfaces.⁽¹¹⁾ Because of a number of processes, however, critically ill patients lose a protective substance called fibronectin from the tooth surface.  Loss of fibronectin reduces the host defence mechanism mediated by reticuloendothelial cells. This reduction in turn results in an environment conducive to attachment of microorganism to buccal and pharyngeal epithelial cells.⁽¹²⁾ Addressing the formation of dental plaque and its continued existence by optimizing oral hygiene in critically ill patients is an important strategy for minimizing VAP.⁽¹³⁾ Two different interventions aimed at decreasing the oral bacterial load are selective decontamination of the digestive tract involving administration of non absorbable antibiotics by mouth, through a naso-gastric tube, and oral decontamination, which is limited to topical oral application of antibiotics or antiseptics.⁽¹⁴⁾ Though meta-analysis of antibiotics in decontamination of digestive tracts have found positive results⁽¹⁵⁾ , the use of this intervention is, however, limited by concern about the emergence of antibiotic resistant bacteria.⁽¹⁶⁾ One alternative to oral decontamination with antibiotics is to use antiseptics, such as chlorhexidine which act rapidly at multiple target sites and accordingly may be less prone to induce drug resistance.⁽¹⁷⁾ Recently a meta-analysis of four trials on chlorhexidine failed to show a significant reduction in rates of ventilator associated pneumonia⁽¹⁸⁾  but, subsequent randomised controlled trials, however, suggested benefit from this approach.⁽¹⁹⁾ Current guidelines from the Centres for Disease Control and Prevention recommend topical oral chlorhexidine 0.12% during the perioperative period for adults undergoing cardiac surgery (grade II evidence). The routine use of antiseptic oral decontamination for the prevention of ventilator associated pneumonia, however, remains unresolved.⁽⁸⁾ Despite the lack of firm evidence favouring this preventive intervention, a recent survey across 59 European intensive care units from five countries showed that 61% of the respondents used oral decontamination with chlorhexidine. As the emphasis on evidence based practice is increasing day by day, integrating recent evidence by meta-analysis could greatly benefit patient care and ensure safer practices. Hence we carried out this meta-analytic review to ascertain the effect of oral decontamination using chlorhexidine in the incidence of ventilator associated pneumonia and mortality in mechanically ventilated adults.⁽²⁰⁾

Methods

Articles published from 1990 to May 2011 in English which were indexed in the following databases were searched: CINAHL, MEDLINE, Joanna Briggs Institute, Cochrane Library, EMBASE, CENTRAL, and Google search engine. We also screened previous meta-analyses and the references lists from all the retrieved articles for additional studies. Further searches were carried out in two trial registers (www.clinicaltrials.gov/ and www.controlled-trials.com/) and on web postings from conference proceedings, abstracts, and poster presentations.

Articles retrieved were assessed for inclusion criteria by three independent reviewers from the field of nursing with masters degrees. The inclusion criteria set for this meta-analysis were as follows:
a) VAP definition meeting both clinical and radiological criteria
b) Intubation for more than 48 hours in ICU.  

We excluded the studies where clinical pulmonary infection score alone was considered for diagnosing VAP. Thereafter the articles were evaluated for randomisation, allocation concealment, blinding techniques, clarity of inclusion and exclusion criteria, outcome definitions, similarity of baseline characteristics, and completeness of follow-up.  We considered randomisation to be true if the allocation sequence was generated using computer programs, random number tables, or random drawing from opaque envelopes. Finally, based on the above characteristics, only 9 trials which fulfilled the inclusion criteria was included for the pooled analysis. A brief summary of the 9 trials were listed in Table 1. The primary outcomes in this meta-analysis were incidence of VAP and mortality rate.

Table 1: Brief summary of trials

NA-Not available; C-Control group; E- Experimental group

Data analysis

Meta-analysis was performed in this study by using Review Manager 4.2 (Cochrane Collaboration, Oxford) with a random effect model. The pooled effects estimates for binary variables were expressed as a relative risk with 95% confidence interval. Differences in estimates of intervention between the treatment and control groups for each hypothesis were tested using a two sided z test. We calculated the number of patients needed to treat (NNT, with 95% confidence interval) to prevent one episode of ventilator associated pneumonia during the period of mechanical ventilation. A chi-squared test was used to assess the heterogeneity of the results. A Forest plot graph was drawn using Stats direct software version 2.72 (England: Stats Direct Ltd. 2008). We considered a two tailed P value of less than 0.05 as significant throughout the study.

Results

Effect of Chlorhexidine in reducing the Incidence of VAP

A total of nine trials were included in this meta-analysis^{(19,21,22,23,24,25,26,27,28)}. Pooled analysis of the nine trials with 2819 patients revealed a significant reduction in the incidence of VAP using chlorhexidine (Relative risk 0.60, 0.47 to 0.76; P< 0.01) (Figure 1). In relation to the Number Needed to Treat (NNT), 21 patients would need to receive oral decontamination with Chlorhexidine to prevent one episode of Ventilator associated pneumonia (NNT 21, 14 to 38).

Figure 1: Forest Plot showing the effect of Chlorhexidine oral decontamination in preventing the incidence of ventilator-associated pneumonia. Test for heterogeneity:χ² =15.5, df =8, p < 0.01. Test for overall effect: z =4.33, p <0.05.

Effect of Chorhexidine in overall mortality rate

For assessing the outcomes in terms of mortality, only seven out of nine trials were included, since the other two^(23,27) did not report the mortality rate. Pooled analysis of the seven trials with 2253 patients revealed no significant effect in reducing the overall mortality rate in patient who received chlorhexidine oral decontamination.(Relative risk 1.02, 0.83 to 1.26; P= 0.781 (Figure 2).

Figure 2: Forest plot showing the effect of Chlorhexidine oral decontamination in reducing overall mortality rate. Test for heterogeneity:χ² =0.05, df =6, p = 0.81. Test for overall effect: z =0.27, p = 0.78

Discussion

The effectiveness of oral decontamination to prevent VAP in patients undergoing mechanical ventilation has remained controversial since its introduction, due to partly discordant results of individual trials. In the present meta-analysis nine trials were included to estimate the pooled effect size; the results revealed a significant reduction in the incidence of VAP among patients who were treated with oral chlorhexidine. But, it had no effect in reducing the overall mortality rate among these patients. There is a firm body of evidence that oropharyngeal colonization is pivotal in the pathogenesis of VAP. More than 25 years ago, Johanson et al described associations between increasing severity of illness, higher occurrence of oropharyngeal colonization, and an increased risk of developing VAP .^(29,30)Subsequently, cohort and sequential colonization analyses identified oropharyngeal colonization as a important risk factor for VAP. ^(31,32,33)  Our finding confirms the pivotal role of Oro- pharyngeal colonization in the pathogenesis of VAP , since this meta-analysis indicates that oral decontamination may reduce  the incidence of VAP. Chlorhexidine was proven to have excellent antibacterial effects, with low antibiotic resistance rates seen in nosocomial pathogens, despite long-term use⁽³⁴⁾.  Previous meta-analyses examining the effect of prophylaxis using selective decontamination of the digestive tract reported a significant reduction in the incidence of ventilator associated pneumonia^(35,36,37). The most recent meta-analysis indicated that such an intervention combined with prophylactic intravenous antibiotics reduces overall mortality⁽³⁸⁾. In comparison our review suggests that oral antiseptic prophylaxis alone can significantly reduce the incidence of ventilator associated pneumonia, but not mortality. A similar result was documented by Ee Yuee Chan et al (2007)⁽¹⁴⁾ who performed a meta-analysis with seven trials with a total of 2144 patients and found a significant result (Odds ratio 0.56, 0.39 to 0.81). Another comparable finding in the present study was,  Mortality rate was not influenced by use of Chlorhexidine use,  which was in line with the findings of Ee Yuee Chan et al (2007)⁽¹⁴⁾ . Our meta-analysis on Chorhexidine differs from the findings of Pineda et al, who pooled four trials on chlorhexidine  and did not report lower rates of ventilator associated pneumonia (odds ratio 0.42, 0.16-1.06; P=0.07)⁽¹⁸⁾ . Our results also extend those of Chlebicki et al, who did not find a statistically significant benefit using the more conservative random effects model after pooling seven trials on chlorhexidine (relative risk 0.70, 0.47- 1.04; P=0.07), although their results were significant with the fixed effects model⁽³⁹⁾. Our meta-analysis included larger data set with a total of 9 trials including recent trials⁽²⁸⁾ which further adds strength to our analysis.

Limitations

Though our literature search was comprehensive, it is possible that we missed other relevant trials. Electronic and hand searches do not completely reflect the extent of research outcomes. For example, trials reported at conferences are more likely than trials published in journals to contain negative reports. In addition, more positive than negative results tend to be reported in the literature. This failure to publish more studies with negative outcomes is probably more due to authors’ lack of inclination to submit such manuscripts than to the unwillingness of editors to accept such manuscripts. Furthermore, many studies not published in English were not included e.g. a study by Zamora Zamora F (2011).⁽⁴⁰⁾ These limitations may lead to a risk for systematic reviews to yield a less balanced analysis and may therefore affect the recommendations resulting from the reviews.  In addition, the heterogeneity which we found among the trials with respect to populations enrolled, regimens used, outcome definitions, and analysis strategies, may limit the ability to generalize results to specific populations.

Conclusion

The finding that chlorhexidine oral decontamination can reduce the incidence of ventilator associated pneumonia could have important implications for lower healthcare costs and a reduced risk of antibiotic resistance compared with the use of antibiotics. These results should be interpreted in light of the moderate heterogeneity of individual trial results and possible publication bias. It may not be prudent to adopt this practice routinely for all critically ill patients until strong data on the long term risk of selecting antiseptic and antibiotic resistant organisms are available. Nevertheless, Chlorhexidine oral decontamination seems promising. Further studies are clearly needed in testing the effect of Chlorhexidine in specific populations with standard protocols (which includes specific concentration, frequency, and type of agents) to generalize the findings. Studies also may be done to test the effect of different oral antiseptics in reducing VAP, so as to enrich the body of knowledge within this area.

Background

Nerve blocks have a variety of applications in anaesthesia enabling an extra dimension for patients with regards to their pain control and anaesthetic plan.  Anaesthetists can perform nerve blocks by a range of methods including landmark techniques and ultrasound guidance, with both of these techniques having the potential to be used with a nerve stimulator.

Nerve blocks are associated with complications including nerve damage, bleeding, pneumothorax and failure.  Ultrasound, if used correctly, may help limit such complications.¹ NICE guidance on the use of ultrasound guidance for procedures, has evolved over the years.  Ultrasound guidance is now considered an essential requirement for the placement of central venous lines² and is recommended when performing nerve blocks.³

Method

This survey aimed to assess the methods used by anaesthetists in performing nerve blocks and audited the use and competencies of clinicians in performing such blocks under ultrasound guidance and landmark techniques. This survey also looked at whether performing nerve blocks under ultrasound guidance was hindered by the lack of availability of appropriate resolution ultrasound machines in the workplace.

A paper survey was completed by anaesthetists of all grades at Kettering general hospital, UK and Birmingham Heartlands Hospital, UK between October and December 2011.  The survey consisted of a simple, easy to use, tick box table and a generic area in which participants made further contributions.  From this we ascertained the following:

• Grade of clinician.
• Any courses undertaken in ultrasound guided nerve blocks.
• Which nerve blocks the clinicians felt they could perform competently with either method (landmark versus ultrasound guided).
• In the event the anaesthetist could perform a block with or without ultrasound guidance; which method was used if ultrasound equipment was available.
• Was the ability to perform ultrasound guided nerve blocks limited by the availability of an ultrasound machine.

The term “landmark technique” is used when the landmark technique is combined with or without a nerve stimulator and the term “ultrasound technique” when ultrasound guidance is used with or without a nerve stimulator.

Results

We surveyed a total of 52 anaesthetists, subdivided into Consultants 26 (50%), ST/staff grade 17 (33%), CT trainees 9 (17%).  Of all grades, only 50% had completed a course in ultrasound guided nerve blocks.  42% of clinicians had encountered situations when they could not use ultrasound guidance for a nerve block because there was no ultrasound machine available at the time of the procedure. 

The competencies of clinicians with the landmark and ultrasound technique varied depending on the type of nerve block and the grade of clinician (figure 1). 

Various routinely performed blocks were surveyed and this revealed a good comparison of the use of ultrasound and landmark technique.  For the Interscalene block, the consultants and middle grades combined were competent in performing this block, with the landmark technique 56% and the ultrasound technique 33%.  For the Lumbar plexus block, 0% of the consultants surveyed felt competent in performing this block with the ultrasound technique compared to 73% with the landmark technique. The majority of clinicians felt competent in performing the TAP block with the ultrasound technique, 65% versus 35%, for the landmark technique.

Figure 1. This table illustrates competencies for different nerve blocks with the landmark technique and ultrasound technique for different grades of anaesthetists.

Discussion

The findings of this survey and audit have a range of implications for anaesthetists in the workplace: 

1) Junior grades of doctors do not feel competent in performing nerve blocks.  This may lead to a reliance on senior doctors during on calls to assist in performing blocks such as femoral and TAP blocks.  Specific training geared towards junior doctors to make them proficient in such blocks would enable them to provide an anaesthetic plan with more autonomy.

2) A large percentage of consultant grade clinicians felt competent in performing nerve blocks with the landmark technique but not in performing the same blocks with ultrasound guidance.  This has implications for training because consultants are the training leads for junior grades of anaesthetists.  If consultants do not feel competent in the use of ultrasound guidance for nerve blocks, this could lead to a self perpetuating cycle.

3) Only 50% of clinicians in this survey had completed a course for ultrasound guided nerve blocks, this coupled with the finding that clinicians did not feel comfortable in performing nerve blocks with ultrasound, indicates the possible need for local training accessible to clinicians to improve their everyday practice.

4) It has been shown that ultrasonic guidance improves the success rate of interscalene blocks.⁴  The practice amongst clinicians in this survey reveals that the majority of anaesthetists (middle and consultant grades) are competent with the landmark technique 56% compared to the ultrasound technique 36%.  This also highlights a training deficit which if addressed would enable clinicians to offer a more successful method of performing the interscalene block.

5) This survey highlighted the lack of availability of appropriate ultrasound machines in different departments, leading to some clinicians utilising the landmark technique, when ultrasound guidance was the preference.  This has the potential of a patient receiving a nerve block technique which may have been riskier and less efficient.  This highlights a potential need for investment and accessibility of appropriate resolution ultrasound machines in the different work places of a hospital environment.

The main limitation of this project was the small number of clinicians in the respective hospitals the survey was performed in.  However, we feel the results reflect the practice of clinicians across most anaesthetic departments.  The recommendations highlight a training need for anaesthetic trainees in the use of ultrasound guided nerve blocks.   This survey could form the basis of a much larger survey of clinicians across the UK to provide a more insightful review of the competencies and preferences of anaesthetic trainees in performing nerve blocks and the availability of appropriate resolution ultrasound machines.

The difference in the number of clinicians in each category limited comparisons between groups.  A larger cohort of participants would enable comparison of nerve block techniques between different grades of clinicians.

This survey included all clinicians regardless of their sub-specialist interest.  This may result in a skewing of results, depending on the area of interest of the clinicians surveyed.

This work only highlights the competencies and preferences of clinicians in performing nerve blocks.  No extrapolation can be made to complications that arise from the choice of either technique.  Studies have shown an improved success rate when performing nerve blocks with ultrasound.⁴ However this does not directly apply to a specific clinician who may have substantial experience in their method of choice in performing a nerve block.

Introduction

Normal sleep is divided into Non-REM and REM. REM occurs every 90-120 minutes during adult sleep throughout the night with each period of REM progressing in length such that the REM periods in the early morning hours are the longest and may last from 30-60 minutes. Overall, REM accounts for 20-25% of the sleep time but is weighted toward the second half of the night. During REM sleep with polysomnography monitoring one observes a low voltage mixed frequency amplitude EEG and low voltage EMG in the chin associated with intermittent bursts of rapid eye movements. During the periods of REM breathing becomes irregular, blood pressure rises and the heart rate also increases due to excess adrenergic activity. The brain is highly active during REM and the electrical activity recorded in the brain by EEG during REM sleep is similar to that of wakefulness.

Parasomnias are undesirable, unexpected, abnormal behavioral phenomena that occur during sleep. There are three broad categories in parasomnias. They are 

1. Disorders of Arousal (from Non-REM sleep)
2. Parasomnias usually associated with REM sleep, and
3. Other parasomnias which also includes secondary type of parasomnias.

RBD is the only parasomnia which requires polysomnographic testing as part of the essential diagnostic criteria.

Definition of RBD

“RBD is characterized by the intermittent loss of REM sleep electromyographic (EMG) atonia and by the appearance of elaborate motor activity associated with dream mentation” (ICSD-2).¹ These motor phenomena may be complex and highly integrated and often are associated with emotionally charged utterances and physically violent or vigorous activities. RBD was first recognized and described by Schenck CH et al. in 1986.² This diagnosis was first incorporated in the International Classification of Sleep Disorders (ICSD) in 1990. (American Academy of Sleep Medicine)

A defining feature of normal REM sleep is active paralysis of all somatic musculature (sparing the diaphragm to permit ventilation). This result in diffuse hypotonia of the skeletal muscles inhibiting the enactment of dreams associated with REM sleep. In RBD there is an intermittent loss of muscle atonia during REM sleep that can be objectively measured with EMG as intense phasic motor activity (figure 1 and 2).

Figure 1

Figure 2

This loss of inhibition often precedes the complex motor behaviors during REM sleep. Additionally, RBD patients will report that their dream content is often very violent or vigorous dream enacting behaviors include talking, yelling, punching, kicking, sitting, jumping from bed, arm flailing and grabbing etc. and most often the sufferer will upon waking from the dream immediately report a clear memory of the dream which coincides very well with the high amplitude violent defensive activity witnessed. This complex motor activity may result in a serious injury to the dreamer or bed partner that then prompts the evaluation.

Prevalence

The Prevalence of RBD is about 0.5% in general population.^{1, 3} RBD preferentially affect elderly men (in 6^th and 7^th decade) with ratio of women to men being 1 to 9.⁴ The mean age of disease onset is 60.9 years and at diagnosis is 64.4 years.⁵ RBD was reported in an 18 year old female with Juvenile Parkinson disease,⁶ so age and gender are not absolute criteria.

In Parkinson disease (PD) the reported prevalence ranges from 13-50%,^{7, 14-19} LewyBody Dementia (DLB) 95%,⁸ and Multiple System Atrophy (MSA) 90 %.⁹ The presence of RBD is a major diagnostic criterion for MSA. RBD has been reported in Juvenile Parkinson disease, and pure autonomic failure^10-12 all neurodegenerative disorders are synucleinopathies.¹³

Physiology

The neurons of locus coeruleus, raphe nuclei, tuberomammillary nucleus, pedunculopontine nucleus, laterodorsal tegmental area and the perifornical area are firing at a high rate, and cause arousal by activating the cerebral cortex. During REM sleep, the aforementioned excitatory areas fall silent with the exception of the pedunculopontine nucleus and laterodorsal tegmental areas. These regions project to the thalamus and activate the cortex during REM sleep. This cortical activation is associated with dreaming in REM. Descending excitatory fibers from the pedunculopontine nucleus and laterodorsal tegmental area innervate the medial medulla, which then sends inhibitory projections to motor neurons producing the skeletal muscle atonia of REM sleep.^20-21

There are two distinct neural systems which collaborate in the “paralysis” of normal REM sleep, one is mediated through the active inhibition by neurons in the nucleus reticularis magnocellularis in the medulla via the ventrolateral reticulospinal tract synapsing on the spinal motor neurons and the other system suppresses locomotor activity and is located in pontine region.²²

Pathophysiology

REM sleep contains two types of variables, tonic (occurring throughout the REM period), and phasic (occurring intermittently during a REM period). Tonic elements include desynchronized EEG and somatic muscle atonia (sparing the diaphragm). Phasic elements include rapid eye movements, middle ear muscle activity and extremity twitches. The tonic electromyogram suppression of REM sleep is the result of active inhibition of motor activity originating in the perilocus coeruleus region and terminating in the anterior horn cells via the medullary reticularis magnocellularis nucleus.

In RBD, the observed motor activity may result from either impairment of tonic REM muscle atonia or from increase phasic locomotor drive during REM sleep. One mechanism by which RBD results is the disruption in neurotransmission in the brainstem, particularly at the level of the pedunculopontine nucleus.²³Pathogenetically, reduced striatal dopaminergic mediation has been found^24-25 in those with RBD. Neuroimaging studies support dopaminergic abnormalities.

Types of RBD

RBD can be categorized based on severity:

1. Mild RBD occurring less than once per month,
2. Moderate RBD occurring more than once per month but less than once per week, associated with physical discomfort to the patient or bed partner, and
3. Severe RBD occurring more than once per week, associated with physical injury to patient or bed partner.

RBD can be categorized based on duration:

1. Acute presenting with one month or less,
2. Subacute with more than one month but less than 6 months,
3. Chronic with 6 months or more of symptoms prior to presentation.

Acute RBD: In 55 - 60% of patients with RBD the cause is unknown, but in 40 - 45% the RBD is secondary to another condition. Acute onset RBD is almost always induced or exacerbated by medications (especially Tri-Cyclic Antidepressants, Selective Serotonin Reuptake Inhibitors, Mono-Amine Oxidase Inhibitors, Serotonin Norepinephrine Reuptake Inhibitors,²⁶ Mirtazapine, Selegiline, and Biperiden) or during withdrawal of alcohol, barbiturates, benzodiazepine or meprobamate. Selegiline may trigger RBD in patients with Parkinson disease. Cholinergic treatment of Alzheimer’s disease may trigger RBD.

Chronic RBD: The chronic form of RBD was initially thought to be idiopathic; however long term follow up has shown that many eventually exhibit signs and symptoms of a degenerative neurologic disorder. One recent retrospective study of 44 consecutive patients diagnosed with idiopathic RBD demonstrated that 45% (20 patients) subsequently developed a neurodegenerative disorder, most commonly Parkinson disease (PD) or Lewy body dementia, after a mean of 11.5 years from reported symptoms onset and 5.1 years after RBD diagnosis.²⁷

The relationship between RBD and PD is complex and not all persons with RBD develop PD. In one study of 29 men presenting with RBD followed prospectively, the incidence of PD was 38% at 5 years and 65% after 12 years.^{7, 28, 29} Contrast this with the prevalence of the condition in multiple system atrophy, where RBD is one of the primary symptoms occurring in 90% of cases.⁹ In cases of RBD, it is absolutely necessary not only to exclude any underlying neurodegenerative disease process but also to monitor for the development of one over time in follow up visits.

Clinical manifestations

Sufferers of RBD usually present to the doctor with complaints of sleep related injury or fear of injury as a result of dramatic violent, potentially dangerous motor activity during sleep. 96% of patients reporting harm to themselves or their bed partner. Behaviors during dreaming described include talking, yelling, swearing, grabbing, punching, kicking, jumping or running out of the bed. One clinical clue of the source of the sleep related injury is the timing of the behaviors. Because RBD occurs during REM sleep, it typically appears at least 90 minutes after falling asleep and is most often noted during the second half of the night when REM sleep is more abundant.

One fourth of subjects who develop RBD have prodromal symptoms several years prior to the diagnosis. These symptoms may consist of twitching during REM sleep but may also include other types of simple motor movements and sleep talking or yelling.^30-31 Day time somnolence and fatigue are rare because gross sleep architecture and the sleep-wake cycle remain largely normal.

RBD in other neurological disorders and Narcolepsy:

RBD has also been reported in other neurologic diseases such as Multiple Sclerosis, vascular encephalopathies, ischemic brain stem lesions, brain stem tumors, Guillain-Barre syndrome, mitochondrial encephalopathy, normal pressure hydrocephalus, subdural hemorrhage, and Tourette’s syndrome. In most of these there is likely a lesion affecting the primary regulatory centers for REM atonia.

RBD is particularly frequent in Narcolepsy. One study found 36% pts with Narcolepsy had symptoms suggestive of RBD. Unlike idiopathic RBD, women with narcolepsy are as likely to have RBD as men, and the mean age was found to be 41 years.³² While the mechanism allowing for RBD is not understood in this population, narcolepsy is considered a disorder of REM state disassociation. Cataplexy is paralysis of skeletal muscles in the setting of wakefulness and often is triggered by strong emotions such as humor. In narcoleptics who regularly experienced cataplexy, 68% reported RBD symptoms, compared to 14% of those who never or rarely experienced cataplexy.^32-33 There is evidence of a profound loss of hypocretin in the hypothalamus of the narcoleptics with cataplexy and this may be a link that needs further investigation in the understanding of the mechanism of RBD in Narcolepsy with cataplexy. It is prudent to follow Narcoleptics and questioned about symptoms of RBD and treated accordingly, especially those with cataplexy and other associated symptoms.

Diagnostic criteria for REM Behavior Disorder(ICSD-2: ICD-9 code: 327.42)¹

A. Presence of REM sleep without Atonia: the EMG finding of excessive amounts of sustained or intermittent elevation of submental EMG tone or excessive phasic submental or (upper or lower) limb EMG twitching (figure 1 and 2).

B. At least one of the following is present:

i. Sleep related injurious, potentially injurious, or disruptive behaviors by history

ii. Abnormal REM sleep behaviors documented during polysomnographic monitoring

C. Absence of EEG epileptiform activity during REM sleep unless RBD can be clearly distinguished from any concurrent REM sleep-related seizure disorder.

D. The sleep disturbance is not better explained by another sleep disorder, medical or neurologic disorder, mental disorder, medication use, or substance use disorder.

Differential diagnosis

Several sleep disorders causing behaviors in sleep can be considered in the differential diagnosis, such as sleep walking (somnambulism), sleep terrors, nocturnal seizures, nightmares, psychogenic dissociative states, post-traumatic stress disorder, nocturnal panic disorder, delirium and malingering. RBD may be triggered by sleep apnea and has been described as triggered by nocturnal gastroesophageal reflux disease.

Evaluation and Diagnosis

• Detailed history of the sleep wake complaints
• Information from a bed partner is most valuable
• Thorough medical, neurological, and psychiatric history and examination
• Screening for alcohol and substance use
• Review of all medications
• PSG (mandatory): The polysomnographic study should be more extensive, with an expanded EEG montage, monitors for movements of all four extremities, continuous technologist observation and continuous video recording with good sound and visual quality to allow capture of any sleep related behaviors
• Multiple Sleep Latency Test (MSLT): Only recommended in the setting of suspected coexisting Narcolepsy
• Brain imaging (CT or MRI) is mandatory if there is suspicion of underlying neurodegenerative disease.

Management

RBD may have legal consequences or can be associated with substantial relationship strain; therefore accurate diagnosis and adequate treatment is important, which includes non-pharmacological and pharmacological management.

Non-pharmacological management: Acute form appears to be self-limited following discontinuation of the offending medication or completion of withdrawal treatment. For chronic forms, protective measures during sleep are warranted to minimize the risks for injury to patient and bed partner. These patients are at fall risk due to physical limitations and use of medications. Protective measure such as removing bed stands, bedposts, low dressers and applying heavy curtains to windows. In extreme cases, placing the mattress on the floor to prevent falls from the bed has been successful.

Pharmacological management: Clonazepam is highly effective in treatment and it is the drug of choice. A very low dose will resolve symptoms in 87 to 90% of patients.^{4, 5, 7-34} Recommended treatment is 0.5 mg Clonazepam 30 minutes prior to bed time and for more than 90% of patients this dose remains effective without tachyphylaxis. In the setting of breakthrough symptoms the dose can be slowly titrated up to 2.0 mg. The mechanism of action is not well understood but clonazepam appears to decrease REM sleep phasic activity but has no effect on REM sleep atonia.³⁵

Melatonin is also effective and can be used as monotherapy or in conjunction with clonazepam. The suggested dose is 3 to 12 mg at bed time. Pramipexole may also be effective^36-38 and suggested for use when clonazepam is contraindicated or ineffective. It is interesting to note that during holidays from the drug, the RBD can take several weeks to recur. Management of patients with concomitant disorder like narcolepsy, depression, dementia, Parkinson disease and Parkinsonism can be very challenging, because medications such as SSRIs, selegiline and cholinergic medications used to treat these disorders, can cause or exacerbate RBD. RBD associated with Narcolepsy, clonazepam is usually added in management and it is fairly effective.

Follow-up

Because RBD may occur in association with neurodegenerative disorder, it is important to consult a neurologist for every patient with RBD as early as possible, especially to diagnose and provide care plan for neurodegenerative disorder, which includes but not limited to early diagnosis and management, regular follow up, optimization of management to provide better quality of life and address medico-legal issues.

Prognosis

In acute and idiopathic chronic RBD, the prognosis with treatment is excellent. In the secondary chronic form, prognosis parallels that of the underlying neurologic disorder. Treatment of RBD should be continued indefinitely, as violent behaviors and nightmares promptly reoccur with discontinuation of medication in almost all patients.

Conclusions

RBD and neurodegenerative diseases are closely interconnected. RBD often antedates the development of a neurodegenerative disorder; diagnosis of idiopathic RBD portends a risk of greater than 45% for future development of a clinically defined neurodegenerative disease. Once identified, close follow-up of patients with idiopathic RBD could enable early detection of neurodegenerative diseases. Treatment for RBD is available and effective for the vast majority of cases.

Key Points

• Early diagnosis of RBD is of paramount importance
• Polysomnogram is an essential diagnostic element
• Effective treatment is available
• Early treatment is essential in preventing injuries to patient and bed partner
• Apparent idiopathic form may precede development of Neurodegenerative disorder by decades

Saliva is the watery and usually frothy substance produced in and secreted from the three paired major salivary (parotid, submandibular and sublingual) glands and several hundred minor salivary glands, composed mostly of water, but also includes electrolytes, mucus, antibacterial compounds, and various enzymes. Healthy persons are estimated to produce 0.75 to 1.5 liters of saliva per day. At least 90% of the daily salivary production comes from the major salivary glands while the minor salivary glands produce about 10%. On stimulation (olfactory, tactile or gustatory), salivary flow increases five fold, with the parotid glands providing the preponderance of saliva.¹

Saliva is a major protector of the tissues and organs of the mouth. In its absence both the hard and soft tissues of the oral cavity may be severely damaged, with an increase in ulceration, infections, such as candidiasis, and dental decay. Saliva is composed of serous part (alpha amylase) and a mucus component, which acts as a lubricant. It is saturated with calcium and phosphate and is necessary for maintaining healthy teeth. The bicarbonate content of saliva enables it to buffer and produce the condition necessary for the digestion of plaque which holds acids in contact with the teeth. Moreover, saliva helps with bolus formation and lubricates the throat for the easy passage of food. The organic and inorganic components of salivary secretion have got a protective potential. They act as barrier to irritants and a means of removing cellular and bacterial debris. Saliva contains various components involved in defence against bacterial and viral invasion, including mucins, lipids, secretory immunoglobulins, lysozymes, lactoferrin, salivary peroxidise, and myeloperoxidase. Salivary pH is about 6-7, favouring digestive action of salivary enzyme, alpha amylase, devoted to starch digestion.

Image -1. (Source of this image- http://www.entdoctor.co.nz)

Salivary glands are innervated by the parasympathetic and sympathetic nervous system. Parasympathetic postganglionic cholinergic nerve fibers supply cells of both the secretory end-piece and ducts and stimulate the rate of salivary secretion, inducing the formation of large amounts of a low-protein, serous saliva. Sympathetic stimulation promotes saliva flow through muscle contractions at salivary ducts. In this regard both parasympathetic and sympathetic stimuli result in an increase in salivary gland secretions. The sympathetic nervous system also affects salivary gland secretions indirectly by innervating the blood vessels that supply the glands.

Table 1: Functions of saliva

Drooling (also known as driveling, ptyalism, sialorrhea, or slobbering) is when saliva flows outside the mouth, defined as “saliva beyond the margin of the lip”. This condition is normal in infants but usually stops by 15 to 18 months of age. Sialorrhea after four years of age generally is considered to be pathologic. The prevalence of drooling of saliva in the chronic neurological patients is high, with impairment of social integration and difficulties to perform oral motor activities during eating and speech, with repercussion in quality of lifeDrooling occurs in about one in two patients affected with motor neuron disease and one in five needs continuous saliva elimination⁷, its prevalence is about 70% in Parkinson disease⁸, and between 10 to 80% in patients with cerebral palsy⁹.

Pathophysiology

Pathophysiology of drooling is multifactorial. It is generally caused by conditions resulting in

1. Excess production of saliva- due to local or systemic causes (table 2)
2. Inability to retain saliva within the mouth- poor head control, constant open mouth, poor lip control, disorganized tongue mobility, decreased tactile sensation, macroglossia, dental malocclusion, nasal obstruction.
3. Problems with swallowing- resulting in excess pooling of saliva in the anterior portion of the oral cavity e.g. lack of awareness of the build-up of saliva in the mouth, infrequent swallowing, and inefficient swallowing.

Drooling is mainly due to neurological disturbance and less frequently to hyper salivation.Under normal circumstances, persons are able to compensate for increased salivation by swallowing. However, sensory dysfunction may decrease a person’s ability to recognize drooling and anatomic or motor dysfunction of swallowing may impede the ability to manage increased secretion.

Table 2 Aetiology of hypersalivation

Depending on duration of drooling, it can be classified as acute e.g. during infections (epiglottitis, peritonsilar abscess) or chronicneurological causes.

Symptoms

Drooling of saliva can affect patient and/or their carers quality of life and it is important to assess the rate and severity of symptoms and its impact on their life.

Table 3 Effect of untreated Drooling of saliva

Assessment

Assessment of the severity of drooling and its impact on quality of life for the patient and their carers help to establish a prognosis and to decide the therapeutic regimen. A variety of subjective and objective methods for assessment of sialorrhoea have been described³.

History (from patient and carers)

Establish possible cause, severity, complications and possibility of improvement, age and mental status of patient, chronicity of problems, associated neurological conditions, timing, provoking factors, estimation of quantity of saliva – use of bibs, clothing changing required/ day and impact on the day today life (patient/carer)

Physical examination

Evaluate level of alertness, emotional state, hydration status, hunger, head posture

Examination of oral cavity- sores on the lip or chin, dental problems, tongue control, swallowing ability, nasal airway obstruction, decreased intraoral sensitivity, assessment of health status of teeth, gum, oral mucosa, tonsils, anatomical closure of oral cavity, tongue size and movement, jaw stability. Assessment of swallowing

Assess severity and frequency of drooling (as per table 4)

Investigation

• Lateral neck x ray (in peritonsilar abscess)
• Ultrasound to diagnose local abscess
• Barium swallow to diagnose swallowing difficulties
• Audiogram- to rule out conductive deafness associated with oropharyngeal conditions
• Salivary gland scan- to determine functional status

Table 4 : System for assessment of frequency and severity of drooling

Management

Drooling of saliva, a challenging condition, is better managed with a multidisciplinary team approach. The team includes primary care physician, speech therapist, occupational therapist, dentist, orthodontist, otolaryngologist, paediatrician and neurologist. After initial assessment, a management plan can be made with the patient. The person/ carer should understand the goal of treating drooling is a reduction in excessive salivary flow, while maintaining a moist and healthy oral cavity. Avoidance of xerostomia (dry mouth) is important.

There are two main approaches

1. Non invasive modalities e.g. oral motor therapy, pharmacological therapy
2. Invasive modalities e.g. surgery and radiotherapy

No single approach is totally effective and treatment is usually a combination of these techniques. The first step in management of drooling is correction of reversible causes. Less invasive and reversible methods, namely oral motor therapy and medication are usually implemented before surgery is undertaken⁵

Non invasive modalities

Positioningprior to implementation of any therapy, it is essential to look at the position of the patient. When seated, a person should be fully supported and comfortable. Good posture with proper trunk and head control provides the basis for improving oral control of drooling and swallowing.

Eating and drinking skills-drooling can be exacerbated by pooreating skills. Special attention and developing better techniques in lip closure, tongue movement and swallowing may lead to improvements of some extent. Acidic fruits and alcohol stimulate further saliva production, so avoiding them will help to control drooling¹⁰

Oral facial facilitation - this technique will help to improve oral motor control, sensory awareness and frequency of swallowing.Scott and staios et al ¹⁸ noted improvement in drooling in patients with both hyper and hypo tonic muscles using this technique. This includes different techniques normally undertaken by speech therapist, which improves muscle tone and saliva control. Most studies show short term benefit with little benefit in long run. This technique can be practiced easily, with no side effects and can be ceased if no benefits noted.
 

a) Icing – effect usually last up to 5-30 minutes. Improves tone, swallow reflex.

b) Brushing- as effect can be seen up to 20- 30 minutes, suggested to undertake before meals.

c) Vibration- improves tone in high tone muscles

d) Manipulation – like tapping, stroking, patting, firm pressure directly to muscles using fingertips known to improve oral awareness.

e) Oral motor sensory exercise - includes lip and tongue exercises.

Speech therapy-speech therapy should be started early to obtain good results. The goal is to improve jaw stability and closure, to increase tongue mobility, strength and positioning, to improve lip closure (especially during swallowing) and to decrease nasal regurgitation during swallowing.

Behaviour therapy-this uses a combination of cueing, overcorrection, and positive and negative reinforcement to help drooling. Suggested behaviours, like swallowing and mouth wiping are encouraged, whereas open mouth and thumb sucking are discouraged. Behavior modification is useful to achieve (1) increased awareness of the mouth and its functions, (2) increased frequency of swallowing, (3) increased swallowing skills. This can be done by family members and friends. Although there is no randomized controlled trial done, over 17 articles published in last 25 years, show promising results and improved quality of life. No reported side effects make behavioural interventions an initial option compared to surgery, botulinum toxin or pharmaceutical management. Behaviour interventions are useful prior and after medical management such as botulinum toxin or surgery.

Oral prosthetic device- variety of prosthetic devices can be beneficial, e.g. chin cup and dental appliances, to achieve mandibular stability, better lip closure, tongue position and swallowing. Cooperation and comfort of the patient is essential for better results.

Pharmacological methods

Systematic review of anticholinergic drugs, show Benztropine, Glycopyrrolate, and Benzhexol Hydrochloride, as being effective in the treatment of drooling. But these drugs have adverse side-effects and none of the drugs been identified as superior.

Hyoscine- The effect of oral anticholinergic drugs has been limited in the treatment of drooling. Transdermal scopolamine (1.5 mg/2.5 cm2) offers advantages. One single application is considered to render a stable serum concentration for 3 days. Transdermal scopolamine has been shown to be very useful in the management of drooling, particularly in patients with neurological or neuropsychiatric disturbances or severe developmental disordersIt releases scopolamine through the skin into the bloodstream.

Glycopyrrolatestudies have shown 70-90% response rates but with a high side effect rate. Approximately 30-35% of patients choose to discontinue due to unacceptable side effects such as excessive dry mouth, urinary retention, decreased sweating, skin flushing, irritability and behavior changes. A study on 38 patients with drooling due to neurological deficits had shown up to a 90% response rateMier et al²¹ reported Glycopyrrolate to be effective in the control of excessive sialorrhea in children with developmental disabilities. Approximately 20% of children given glycopyrrolate may experience substantial adverse effects, enough to require discontinuation of medication.

Antimuscarinic drugs, such as benzhexol, have also been used, but limited due to their troublesome side effects.

Antireflux Medication: The role of antireflux medication (Ranitidine & Cisapride) in patients with gastro esophageal reflux due to esophageal dysmotility and lower esophageal tone did not show any benefits in a study ²¹.

Modafinil - One case study noticed decreased drooling in two clients who were using the drug for other reasons, but no further studies have been done.

Alternate medications: (Papaya and Grape seed extract) – Mentioned in literature as being used to dry secretions but no research in to their efficacy has been conducted.

Botulinum toxin It was in 1822 that a German poet and physician, Justinus Kerner, discovered that patients who suffered from botulism complained of severe dryness of mouth which suggested that the toxin causing botulism could be used to treat hypersalivation. However, it was only in the past few years that botulinum toxin type A (BTx-A)has been used for this purpose. BTx-A binds selectively to cholinergic nerve terminals and rapidly attaches to acceptor molecules at the presynaptic nerve surface. This inhibits release of acetylcholine from vesicles, resulting in reduced function of parasympathetic controlled exocrine glands. The blockade though reversible is temporary as new nerve terminals sprout to create new neural connections. Studies have shown that injection of botulinum toxin to parotid and submandibular glands, successfully subsided the symptoms of drooling ^30,31. Although there is wide variation in recommended dosage, most studies suggest that about 30- 40 units of BTx-A injected into the parotid and submandibular glands are enough for the symptoms to subside The injection is usually given under ultrasound guidance to avoid damage to underlying vasculature/ nerves. The main side effects from this form of treatment are dysphagia, due to diffusion into nearby bulbar muscles, weak mastication, parotid gland infection, damage to the facial nerve/artery and dental caries.

Patients with neurological disorders who received BTX-A injections showed a statistically significant effect from BTX-A at 1 month post injection, compared with control, this significance was maintained at 6 months. Intrasalivary gland BTX-A was shown to have a greater effect than scopolamine.

The effects of BTx-A are time limited and this varies between individuals.

Invasive modalities

Surgerycan be performed to remove salivary glands, (most surgical procedures focused on parotid and submandibular glands). ligate or reroute salivary gland ducts, or interrupt parasympathetic nerve supply to glands. Wilke, a Canadian plastic surgeon, was the first to propose and carry out parotid duct relocation to the tonsillar fossae to manage drooling in patients with cerebral palsy. One of the best studied procedures, with a large number of patients and long term follow up data, is submandibular duct relocation ^{32, 33}.

Intraductal laser photocoagulation of the bilateral parotid ducts has been developed as a less invasive means of surgical therapy. Early reports have shown some impressive results^34.

Overall surgery reducedsalivary flow and drooling can be significantly improved often with immediate results – 3 studies noted that 80 – 89% of participants had an improvement in their control of their saliva. Two studies discussed changes in quality of life. One of these found that 80% of those who participated improved across a number of different measures including receiving affection from others and opportunities for communication and interaction. Most evidence regarding surgical outcomesof sialorrhea management is low quality and heterogeneous. Despitethis, most patients experience a subjective improvement followingsurgical treatment ³⁶.

Radiotherapy - to major salivary glands in doses of 6000 rad or more is effective Side effects which include xerostomia, mucositis, dental caries, osteoradionecrosis, may limit its use.

Chronic pain, arbitrarily defined as that lasting longer than six months, is a clinical, social, and economic problem. It is often accompanied by feelings of low mood and despondency.

Whether chronic pain induces clinical depression or depression initiates psychosomatic pain (through physiological mechanisms) is difficult to prove. The burden of illness increases when patients suffer from both. Financial hardship and medical costs affect the quality of life which leads to difficulties in coping and further decreased functioning, making the treatment of both conditions more complicated. Therefore, better recognition, assessment, and treatment of comorbid pain and depression should, at least in theory, lead to better outcomes.

Pain is broadly categorized into three groups: nociceptive (any painful stimulus), neuropathic (for example, diabetes), and psychogenic. Nociceptive pain occurs with direct noxious stimuli. Neuropathic pain is a result of disease or injury to the nervous system or spinal cord. Psychogenic pain has no discernible physical origin. Although the precise physiological mechanisms are not entirely understood, there are two basic categories of sensory neurones. The first type is myelinated and fast conducting; the second is unmyelinated and slow conducting.

Acute pain which follows damage to tissue (an ankle sprain, for example) is usually correlated with hyperalgesia (an increase in the pain elicited by a noxious stimulus and felt as a sharp, burning sensation) and allodynia (‘other’ pain evoked by a normally innocuous stimulus) and serves to protect the injury from further trauma while allowing the damage to be repaired.

Depression is often a chronic disorder and though its symptoms may be alleviated by appropriate medication and other therapies, physical complaints tend to be more intractable. For example, fibromyalgia (FM), a syndrome characterized by widespread muscle pain and generalized tender points, is often associated with major depressive disorder.¹ However, although the vast majority of patients with fibromyalgia do not meet criteria for a psychiatric disorder, psychological symptoms are common. In a randomized controlled trial of primary care patients with musculoskeletal problems and depression, antidepressant medication followed by a self-management pain programme led to improvement in both.² The tricyclic antidepressant amitriptyline was traditionally used usually in small doses, to treat pain, with moderate success. In addition to its own intrinsic analgesic effect amitriptyline appears to enhance the effects of opioid analgesia. Other antidepressants are now in vogue; for example, duloxetine, a serotonin (5-HT)/noradrenaline (NA) reuptake inhibitor, is sometimes used for diabetic neuropathic pain.

Of the numerous neurotransmitters at least two, namely 5-HT and NA, may prove to be one common link between depression and pain. Both serotoninergic and noradrenergic pathways ascend from subcortical areas (brainstem, hypothalamus and thalamus) to the whole neocortex and mediate emotional and physiological responses.³ Their pathways descend the spinal cord and suppress nociceptive inputs. Serotoninergic cell bodies located in the raphe nucleus in the brainstem, and noradrenergic neurones located in the locus coeruleus (also in the brainstem) send projections to various parts of the brain involved in the control of mood, appetite, sexual activity, attention and concentration. Theoretically at least, a dysfunction at the level of the serotoninergic and noradrenergic neurons could affect both ascending and descending pathways resulting in the psychological and physically painful symptoms of depression. Neurotransmitters may open or close the ‘gate’ on perception of painful stimuli. Therefore adrenergic and serotoninergic pathways from the brainstem to the spinal cord will inhibit incoming painful stimuli. This is perhaps an oversimplification as some sensory fibres enter via the ventral spinal roots.

The hypothalamic pituitary axis (HPA) is probably also involved. The hypothalamus, which synthesises and secretes neurohormones, has a wide range of physiological functions including regulation of thirst and hunger, sexual behaviour, defence reactions such as fear and rage, and circadian rhythm: disturbances of all these functions are frequently seen in depressed or anxious patients. The HPA is also affected in patients with physical stress as well as major depression, as shown by increased levels of adrenocorticotropic hormone and cortisol in the plasma. Stimulation of the lateral areas of the hypothalamus produces a diffuse sympathetic discharge possibly because some areas of the hypothalamus control adrenaline and NA secretion. Prolonged stress associated with pain leads to depletion of central 5-HT and malfunction of other associated receptors.⁴

The hypothalamus and limbic system (whose boundaries are difficult to define) with its associated structures – the amygdala, hippocampus and septal nuclei, are involved in the mental and affective aspects of emotions. The amygdala, a cluster of nuclei in the medial temporal lobe, may have a role in the reciprocal relationship between pain and depression. The amygdala controls not only emotional behaviour but also memory. However, mixed results have been reported regarding the level of activity of the amygdala in response to pain.

Nociceptor afferents terminate within distinct regions of the dorsal horn and within the spinal cord, synapses are sites of considerable modification, hence the term ‘gate’ for the dorsal horn cells. The neurotransmitter for slow pain is believed to be substance P, and glutamate is the putative transmitter secreted by primary afferent fibres subserving fast pain.⁵

5-HT and NA neurotransmitter systems influence neuroplasticity in the brain. Most currently available antidepressants act through reuptake inhibition of either or both. Therefore, it would seem feasible to prescribe dual-action antidepressants when pain symptoms are associated with depression. However depressed patients with pain comorbidity are less likely to take antidepressant medications compared to those with depression alone. Also, individuals who develop pain or depression are at risk for developing the other, thus escalating the clinical management. Furthermore, when pain is refractory to treatment, it is associated with more depressive symptoms and worse depression outcomes, and vice versa. Depressive symptoms are very common in physically ill patients. Unfortunately, depression is often overlooked in pain patients because pain symptoms take priority or worse still, comorbid depression is not considered.

It is difficult to state with certainty whether or not unexplained pain is ‘psychological’. Such an assumption might be perceived as demeaning and patronizing to patients and the suggestion of providing cognitive therapy misinterpreted as him/her overplaying their reaction to pain or that the pain is ‘psychological’. Others do not like being labelled ‘psychiatric’, and are therefore reluctant to take antidepressants even when a physiological explanation is given. Pain perception involves physical and emotional factors and its primary function is to protect the organism from harm. It follows therefore, that pain thresholds and pain tolerance vary from individual to individual, and especially among patients with depression.

Antidepressants are frequently used in the treatment of depression and generalized anxiety disorders. Their use extends beyond these areas, however, and it is now accepted that antidepressants are efficacious in treating chronic pain syndromes in addition to their effects on psychological features such as low mood, inordinate guilt, or feelings of worthlessness. Because physical symptoms are often the main complaint in many depressed patients and pain is common as a presenting symptom, clinicians need to know about the dual use of antidepressants for both. Future antidepressants may involve neurotransmitters, other than 5-HT and NA, which could include dopaminergic pathways, opioid (antagonists of morphine-type drugs) receptors and the pentapeptides (enkephalins) which bind to these receptors.

Introduction

Case presentation

A 52 year-old Caucasian male with a history of chronic obstructive airway disease (COPD) presented to the emergency department complaining of progressive shortness of breath. Two days prior, the patient had presented to the ED with similar complaints that resolved with aerosol treatments and the patient was discharged on a metered dose inhaler (MDI).  The patient had been prescribed MDI’s (metered dose inhalers) previously for management of his COPD, but due to financial constraints he had been unable to fill his prescription for the past month. Emergency medical services (EMS) suspected COPD exacerbation and administered 40 mg prednisone IV and two albuterol-ipratropriumnebulisertreatments en route to the hospital, which improved the patient’s breathing symptoms.                                             

Upon arrival to the hospital, his blood pressure was 129/90, respirations 28, pulse 127, and he had an oxygen saturation of 100% on 7L/min. Physical examination revealed increased work of breathing, and wheezes in all lung fields with prolonged expiratory phase. The cardiovascular exam was normal except for tachycardia.  A Routine electrocardiogram (ECG) revealed sinus tachycardia and T wave inversions in anterior leads. Chest x-ray showed old scarring in the left lower lobe. Routine cardiac enzymes showed mild elevation with a serum troponin level of 0.68ng/ml (normal range 0.0ng/ml-0.05ng/ml). The second set of troponin peaked at 1.66 ng/ml (normal 0.0ng/ml-0.05ng/ml). In view of the elevated cardiac enzymes atransthoracicechocardiogram was performed which demonstrated multiple wall motion abnormalities and reduced left ventricular ejection fraction of 25%. Coronary angiography demonstrated normal coronary arteries. Left ventriculography revealed hypokinetc mid-anterior and apical segment with a hypercontractile base with reduced ejection fraction (EF) of around 25% (normal range EF 55-65%)  (Figure 1)

Figure 1. Left ventriculography demonstrating the classic appearance of Takotsubo cardiomyopathy

In light of the systolic dysfunction not in proportion with the degree of coronary artery stenosis and the multiple areas of wall motion abnormalities seen on echocardiogram, the diagnosis of Takotsubo cardiomyopathy (TCMP) was made. The diagnosis was further supported by the presence of ECG changes, troponin elevation, and the added social stresses of being unemployed. Over the course of his stay in hospital, the patient’s breathing improved with oral prednisone, inhaled tiotropium, and fluticasone/salmeterol. The patient was also treated with an angiotension converting enzyme inhibitor (ACE inhibitor), aspirin, statin, and beta-blockers. There were no adverse coronary events during the course of his hospital stay and the patient was discharged after four days. A Follow up echocardiogram after 4 weeks showed normal left ventricular systolic function.

DISCUSSION

Takotsubo cardiomyopathy (TCMP), also called stress-induced cardiomyopathy, apical ballooning syndrome, or broken heart syndrome, is a transient systolic dysfunction of the ventricles in the absence of significant coronary artery disease. Once thought to be a rare syndrome, TCMP is increasingly being identified in clinical practice, however, the prevalence and incidence are not known. It is estimated that 0.7-2.5% of patients who present with acute coronary syndrome are found to have TCMP¹ .The majority of these patients are postmenopausal females, with a mean age of 62-75 years. They may present with chest pain and have a recent history of an emotional stress or severe medical illness. ¹

The clinical manifestations of TCMP can mimic those of an acute myocardial infarction. Although, chest pain is a common presenting symptom, patients may also have complaints ofdyspnoeaand arrhythmias. In our casedyspnoeawas the predominant symptom and was easily confused with COPD exacerbation. Recently a few cases of concomitant stress cardiomyopathy with obstructive airway disease have been documented in literature. ^2-4 While the pathophysiology of the coexistence of these two disorders is not fully understood, it is thought that both stress induced cardiac dysfunction due to exaggerated sympathetic activation and use of sympathomimetic bronchodilators instigates the myocardial stunning in such patients.  Furthermore, an emotional stressor, such as death of a family member, or a physiological stressor, such as an acute medical illness, is thought to be a trigger for cardiomyopathy. ⁵ It is believed that the syndrome is not a result of anischemia, but there is some evidence to suggest thatoestrogenlevels may have a role in modulating the sympatho-adrenal outflow in TCMP. In mice models, chronic oestrogen supplementation seemed to have protective effects from exaggerated sympathetic outflow from the heart and brain⁶ . Postmenopausal women with low levels ofoestrogenmay be more vulnerable to the exaggerated catecholamine release in responses to stressors. ⁷  

The characteristic finding in TCMP is a transient mid-ventricular or apical ballooning due to a hypokinetic portion seen on echocardiogram or on a left ventriculography. Systolic dysfunction is usually transient, inconsistent to the perfusion area of a single coronary artery, and usually resolves within 4-6 weeks. ⁸ Additional findings include ECG changes with ST segment deviations in precordial leads being the most common. Cardiac enzymes have been noted to have moderate elevations.^9.

As data regarding the treatment of TCMP is limited, medical management mainly consists of symptomatic therapy with aspirin, ACE inhibitors, beta-blockers, and diuretics, also used in acute coronary syndrome.¹⁰   Patients who present acutely are treated as acute coronary syndrome and often receive emergency coronary angiography. However, less invasive imaging techniques, such as echocardiograms, should first be examined carefully.  Due to the transient nature of the syndrome, the duration of treatment is unknown with some studies suggesting that there is no benefit with chronic treatment. ¹¹   The prognosis is fairly good, with in hospital mortality rates being reported to range from 0-8%, and recovery of left ventricular function in the majority of patients. ^{9, 12} 

TCMP is difficult to distinguish from acute coronary syndrome on first presentation. Our patient had significant social stress. She presented with severedyspnoeaand was treated for COPD exacerbation. Elevation of cardiac enzymes and ECG changes lead to further evaluation and diagnosis of stress cardiomyopathy. This atypical presentation of TCMP showcases the importance ofutilisingthe routine noninvasive imaging and laboratory values to guide the diagnosis. Furthermore physicians need to maintain a high clinical suspicion for this syndrome.

Dr James Moon is a Senior Lecturer and Consultant Cardiologist at UCL and the Heart Hospital.  He set up and runs the cardiac MRI department dividing his time between clinical practice and research. 

He is part of a team of 5 research fellows in the new Heart Hospital Imaging department. He is interested in understanding the structure and function of the heart, particularly the heart muscle, and in detecting abnormalities of the heart to better target treatment.

How long have you been working in your speciality?

12 years (3 as consultant)

Which aspect of your work do you find most satisfying?

The creative aspects of research - joining the dots on information that does not fit and constructing a coherent body of work.

What achievements are you most proud of in your medical career?

Changing statin prescribing in England – as a registrar, I did not having access to cardiac MRI for 2 years and I worked relentlessly at all levels of the healthcare system –including up to Commons Health Select Committee - on this with the result that £1billion was saved or diverted to treat more individuals with statins – the UK now has the highest uptake of statins for primary prevention in the world.

Developing new ways of detecting different types of disease with MRI or CT scanners – in its latest iteration, we may be onto a technique that can measure a fundamental process common to most diseases and organs – not just the heart, and with CT as well as MRI: the volume of cells, fibrosis and their ratio.

Which part of your job do you enjoy the least?

New bureaucracy which we did without just a few years ago..

What are your views about the current status of medical training in your country and what do you think needs to change?

I worry about a tickbox ‘learning portfolio’ culture which dumbs down initiative and personal responsibility leaving a misplaced sense of entitlement.

How would you encourage more medical students into entering your speciality?

I’ve not seen the need to – cardiology is a fantastic, over-subscribed specialty with something for everyone so its pretty competitive.  

What qualities do you think a good trainee should possess?

The same as those of a doctor.  I have never seen this trainee:consultant divide; there is a continuum of learning and responsibility development.

What is the most important advice you could offer to a new trainee?

My advice is about learning rather than being a trainee. Medicine does not have that many raw facts to learn. What it does have is interconnected systems. Rarely consciously try and learn information – rather, try and link everything you have ever learned together, preventing isolated islands of knowledge. It takes longer to create the story, but you will never forget it and it’s far more rewarding. If you encounter something new - a tricky JVP waveform, an ECG repolarisation abnormality or some esoteric MRCP clinical sign, invoke your know of the physical world and apply it to explain the new phenomena – write the essay, deconvolute the phenomena and build it back up, perhaps with subtle changes to see where that gets you. You have spent decades  learning about the Krebb’s cycle, anatomy, electron transport, fractals, Newtonian dynamics, Brownian motion, fluid dynamics, conservation of energy, entropy, cell structure, evolutionary biology, statistics etc etc – use them.

What qualities do you think a good trainer should possess?

I am not sure I know, but generating enthusiasm in people, and then rewarding and promoting it - that’s a good starting point.

Do you think doctors are over-regulated compared with other professions?

No.

Is there any aspect of current health policies in your country that are de-professionalising doctors? If yes what shouldbe done to counter this trend?

It’s the effects on individuals that concern me.  I fully understand the need for process, protocol teamwork and hierarchy, but these remove individual responsibility

Which scientific paper/publication has influenced you the most?

The non-medical maths/science/philosophy books and magazines I read at school and university. I particularly remember Martin Gardner recreational maths books.  Recently I have used fractals and the concepts behind trapdoor ciphers in my understanding of cardiology.

What single area of medical research in your speciality should be given priority?

Prioritize individual researchers/teams rather than topics to create progress through their enthusiasm and own perceptions of priorities.

What is the most challenging area in your speciality that needs further development?

Managing our increasing technical capability which comes with ever reducing incremental benefit.

Which changes would substantially improve the quality of healthcare in your country?

I would overhaul the way society pays for and develops drugs. I would focus on increasing drug company reward for the risk associated with genuine innovation whilst reducing reward for expensive ‘me too’ drugs with no added value.  My group estimated that about 10% of the NHS drug budget could immediately be reallocated improving societal value for money in prescribing, paying for all those much needed NICE decision cancer type drugs and concurrently turbocharging rather empty pharmaceutical drug development pipelines.

Do you think doctors can make a valuable contribution to healthcare management?  If so how?

Absolutely. If you have transparently good and altruistic ideas, are selfless about who gets he credit for them, and sufficiently driven to achieve results, the NHS is a wonderful place - its like a demagnetized iron – apply a sufficiently persuasive external field, and the domains line up, generating far more force and direction than expected. 

How has the political environment affected your work?

The UK has been great for my field –new techniques are adopted early and the international bane of my field - cardiology-radiology turf wars are less acrimonious here as socialized medicine does not reimburse on a pay per procedure basis..

What are your interests outside of work?    

My young family, recreational science, cooking.

If you were not a doctor, what would you do?

Who knows.  Perhaps an economist or maybe evolutionary biologist.

Bisphosphonates, which have been on the market for roughly a decade, have raised safety concerns in the past. Several case series and multiple individual case reports suggest that some subtrochanteric and femoral shaft fractures may occur in patients who have been treated with long-term bisphosphonates. Several unique clinical and radiographic features are emerging. Recent media spotlight in the United States (US), implying that long-term use of alendronate could cause spontaneous femur fractures in some women, has reignited the debate about the safety of bisphosphonates. The question posed: is the risk of bisphosphonate-associated fractures so great that treatment should be stopped?
 
Postmenopausal women with osteoporosis are commonly treated with the bisphosphonate class of medications, one of the most frequently prescribed medications in the US. While alendronate therapy has been shown to decrease the risk of vertebral and femoral neck fractures in postmenopausal osteoporotic patients, recent reports have associated long-term alendronate therapy with low-energy subtrochanteric and diaphyseal femoral fractures in a number of patients. In the past four years reports have been published implying that long-term bisphosphonate therapy could be linked to atraumatic femoral diaphyseal fractures.^{1, 2} According to two studies reported recently at the American Association of Orthopedic Surgeons 2010 Annual Meeting, an unusual type of bone fracture has been reported in women who have taken bisphosphonates for osteopenia and osteoporosis for more than four years.^{3, 4} The first report was published in 2005. Odvina et al⁵ reported on nine patients who sustained atypical fractures, including some with delayed healing, while receiving alendronate therapy. These authors raised the concern that long-term bisphosphonate therapy may lead to over-suppression of bone remodelling, an impaired ability to repair skeletal microfractures, and increased skeletal fragility. There have been other reports of "peculiar" fractures - i.e. low-energy femur fractures that are typically transverse or slightly oblique, diaphyseal, or subtrochanteric, with thickened cortices and a unicortical beak - in patients who have been on long-term bisphosphonate treatment.^{1-4, 6}
 
In a small prospective study, Lane et al³ obtained bone biopsies from the lateral femurs of 21 postmenopausal women with femoral fractures. Twelve of the women had been on bisphosphonate therapy for an average duration of 8.5 years, and nine had no history of bisphosphonate use. They found that the heterogeneities of the mineral/matrix ratio were significantly reduced in the bisphosphonate group by 28%, and the crystallinity of the bone was significantly reduced by 33% (p < 0.05). The authors concluded that this suggested suppression of bone turnover, resulting in a loss of heterogeneity of the tissue properties, which may be a contributing factor to the risk of atypical fractures that we are starting to see. It is believed that long-term alendronate administration may inhibit normal repair of microdamage arising from severe suppression of bone turnover (SSBT), which, in turn, results in accumulation of microdamage. This process would lead to brittle bone and the occurrence of unexpected stress fractures, characteristically at the subtrochanter of femur. The typical presentation of these fractures consist of prodromal pain in the affected leg and/or a discrete cortical thickening on the lateral side of the femur in conventional radiological examination or the presentation with a spontaneous transverse subtrochanteric femur with typical features. The morbidity of atypical femoral fractures, particularly when bilateral, is high. Surgical intervention is generally required and healing may not be achieved for several years. Despite the lack of conclusive evidence of a causal relationship with bisphosphonate therapy, the current consensus is that treatment should be discontinued in patients who develop these fractures. In view of the high frequency of bilateral involvement, imaging of the contralateral femoral shaft with X-rays, MRI, or an isotope bone scan should be performed. MRI and bone scanning havegreater sensitivity than radiography for an incipient stressfracture. If lateral cortical thickening and/or an incipient stress fracture is seen, prophylactic surgical fixation should be considered. Suppressed bone formation in these patients provides a possible rationale for the use of anabolic skeletal agents, such as parathyroid hormone peptides, but at the present time the efficacy of this approach remains to be established. Parathyroid hormone not only has activated bone-formation markersin trials in humans but has also enhanced the healing of fracturesin studies in animals.  
                                                                                                                                                     
The question of whether these fractures are causally linked to bisphosphonate therapy is widely debated but as yet unresolved. Consequences of long-term suppression of bone turnover include increased mineralization of bone, alterations in the composition of its mineral/matrix composite and increased micro damage, all of which may reduce bone strength. Whilst these lend biological plausibility to a causal association, however, they do not constitute direct evidence. The bilateral fractures seen in many patients corroborate the suspicion that patients with bisphosphonate-associated stress fractures carry some other risk factor in addition to taking the drug. Microfractures,inadequate mineralization, and outdated collagen are some of the candidate causes. However, until further studies can provide definitive evidenceof bisphosphonate-associated fractures, it is premature to attributeatypical fractures to over-suppression of bone turnover alone,while disregarding secondary and patient-related factors. Many experts believe that prolonged suppression of bone remodelling with alendronate may be associated with a new form of insufficiency fracture of the femur. Studies have not shown if the entire class of medications produce a similar result, but patients who have been treated with any bisphosphonate for an extended period of time should be considered at risk.
 
A wealth of information from well-designed clinical trials clearly shows that, as a class, bisphosphonates are highly effective at limiting the loss of bone mass, deterioration of bone micro architecture, and increased fracture risk that occur with aging. The benefit/risk ratio of bisphosphonate therapy in patients at high risk of fracture remains overwhelmingly positive because of the very low incidence of atypical femoral fractures. Current estimates suggest that alendronate prevents 200 clinical fractures if 4000 women are treated over three years and will cause one femur fracture over the same course of time.⁷ A study by Schilcher et al⁸ found that the incidence density of a stress fracture for a patient on bisphosphonate was 1/1000 per year (95% CI: 0.3-2), which is acceptable considering that bisphosphonate treatment is likely to reduce the incidence density of any fracture by 15/1000.⁹ Nevertheless, limitation of treatment duration to five years in the first instance, with evaluation of the need to continue therapy thereafter, may be appropriate in clinical practice. The Fracture Intervention Trial Long-term Extension (FLEX), in which postmenopausal women who had received alendronate therapy for five years were randomised to continue receiving alendronate for five additional years or switched to placebo, provided clinical evidence that the effect of bisphosphonate therapy was maintained after discontinuation of therapy.^{7, 10} Women who are being treated with bisphosphonates should take a drug holiday if they have been on them for five years. Patients in whom bisphosphonate therapy is discontinued should typically follow up with bone mineral density measurements at 1- to 2-year intervals, with some experts advocating periodic measurement of biochemical markers of bone turnover to detect loss of the antiresorptive effect. Additional research is necessary to determine the exact correlation between the use of bisphosphonates and spontaneous or low-energy trauma fractures.

 

(A Poem written by a doctor about ADHD)