PERSPECTIVE
Treatment guidelines: implications for community-based headache treatment Tension-type headache (TTH) is the most common form of headache in the community, affecting up to 80% of people from time to time (1). At least 10% of people experience episodic TTH on a frequent basis (up to 14 days per month) and the condition is chronic for 2– 3% (1). The outcome for patients with frequent episodic TTH is generally favourable, as shown in a study by Lyngberg et al. (2). When followed up after 12 years, 45% of patients had infrequent or no headaches (equivalent to remission), 39% still had frequent headache episodes and only 16% experienced chronic TTH. The mechanisms behind TTH are not fully understood because, despite the ubiquitous and disabling nature of this condition, there is a relative lack of research into primary headache disorders in general – and TTH in particular. Peripheral mechanisms seem to have an important role in episodic TTH, which is thought to develop as a result of pain referred from trigger points in pericranial muscles (3), coupled with the sensitisation of muscle nociceptors which causes increased pain sensitivity (4). In addition, in patients with frequent and chronic TTH, the central nervous system is hypersensitive to pain (4). The treatment of TTH ranges from nonpharmacologic therapies to the use of simple and combination analgesics. However, despite the high frequency of TTH and the associated burden on society, the scientific basis for many of the currently used treatment approaches (in particular nonpharmacological treatment) is limited. Several consensus-based treatment guidelines and reference publications are available, for example, from the European Federation of Neurological Societies (EFNS) (5), the Danish Headache Society (4) and the European Headache Federation (EHF) in collaboration with other organisations including the World Health Organisation (1). Effective management of headache disorders is further hampered by a lack of knowledge among healthcare professionals. Worldwide, only 4 h of formal undergraduate training are committed to headache disorders on average, making better professional education about headache disorders a key priority (6).
Non-pharmacological treatment approaches
Most headaches in patients with episodic TTH are mild-to-moderate, and nonpharmacological approaches (Box 1) have a key role in their management (5). European guidelines recommend that nondrug management of TTH should always be considered, despite the sparsity of scientific evidence for most widely used nonpharmacological approaches. (5) When a patient presents in primary care, just listening to the individual and taking their fears and concerns seriously can have a therapeutic effect. Thorough physical examination can also be helpful to reassure patients that their headache does not have a serious/life-threatening cause. Patients also benefit from information about the nature of the condition (5). This could include an explanation of how tension in the muscles of the head and neck acts as the source of a headache episode. Head and neck muscles are linked to peripheral nerves that trigger the characteristic, referred pain of headache. If prolonged, this can lead to a disturbance of the brain’s pain-processing mechanisms so that normally innocuous stimuli are perceived as painful (5) and the headaches become chronic. An important step towards empowering patients to self-manage their condition is the identification of trigger points and protective factors. For this purpose, it is useful if patients complete a headache diary; sample diaries and calendars can be downloaded from the website of the Danish Headache Society (www.dhos.dk). Common triggers of TTH include stress, irregular/inappropriate meals, caffeinated drinks, dehydration, lack of sleep, psycho-behavioural
Successful management of episodic TTH requires a multi-modal approach including use of nonpharmacological therapies and effective analgesics
Box 1. Non-pharmacological treatment of tension-type headache
• • • • • •
ª 2015 John Wiley & Sons Ltd Int J Clin Pract, May 2015, 69 (Suppl. 182), 13–16 doi: 10.1111/ijcp.12652
Physical examination and reassurance Inform the patient about disease mechanisms Minimise, to the extent possible, trigger factors, e.g. stress and unphysiological work postures Physiotherapy (daily exercise programme and posture correction) Biofeedback Stress and pain management
13
14
Perspective
problems, hormonal causes and reduced or inappropriate physical exercise. Other treatment programmes can be recommended based on the patient’s specific history, prior treatment and current diagnosis. Commonly used methods include electromyography biofeedback, relaxation techniques, stress management for preventing headache disorders and cognitive behavioural therapy. Relaxation training involves a range of affective, cognitive and behavioural techniques, such as breathing exercises and meditation. As with biofeedback, the aim is to enable the patient to recognise and control any tension in the head and neck muscles that arises during daily activities. In cognitive behavioural therapy, the patient learns to identify thoughts and beliefs that create stress and may result in headaches. Documented evidence of efficacy is only available for electromyography biofeedback, whereas data for the other methods remain inconclusive (5). Non-invasive physical therapy is also widely used to treat TTH, based on the premise that headache attacks originate in tender muscles of the head and neck (see Box 2 for muscles that can refer pain to the head with active trigger points). A snapping palpation of the muscle can reproduce the patient’s headache by activating local and referred pain pathways (see Figure 1 for the application of pressure points to detect trigger points) (7). Although potentially helpful in diagnosis, there is currently no data to support a role for the direct treatment of trigger points in the management of TTH, for example, using infiltration or local anaesthetics injected into the trigger point itself. Physical therapy includes general muscle treatment (massage, myofascial release, ice/heat and stretching) and release of specific muscle trigger points (trigger point pressure release and dry needling). It is also important to provide instruction on the improvement of posture and training in individual exercises that the patient can carry out at home. Physiotherapy can reduce the number of headache days in TTH by approximately 25% (8). Further research into the benefits of manual therapies is urgently needed (5,9).
Pharmacological treatment approaches The efficacy of pharmacological interventions to treat individual episodes of TTH is well established (5). Table 1 provides an overview of the drugs and doses recommended by the EFNS, based on current evidence. According to the EHF, although drug therapy has limited scope in TTH, it can prove effective in many patients (1). Symptomatic treatment with
over-the-counter analgesics is therefore recommended for episodic tension-type headache occurring on 2 or fewer days per week (1). The available evidence suggests that NSAIDs are more effective than paracetamol, while the latter may have a better gastrointestinal (GI) adverse event profile when compared with prescription-strength NSAIDs (5). In a large-scale meta-analysis evaluating the efficacy of oral agents for the acute treatment of episodic TTH, paracetamol (1000 mg), ibuprofen (400 mg) and ketoprofen (25 mg) were all shown to provide effective pain relief compared with placebo (10). However, it was noted that the available evidence for treatment efficacy in TTH is generally lacking when compared with the overall size of the clinical problem (10). The efficacy of NSAIDs in TTH has been further confirmed by a quantitative and qualitative analysis of 41 randomised, controlled trials (11). This systematic review showed that all types of NSAIDs were more effective than placebo against an acute episode of TTH, but found that no single NSAID was more effective than another (11). Among NSAIDs, ibuprofen has the most favourable GI tolerability profile and is therefore recommended by the EFNS as the drug of choice for TTH (4). Data from clinical trials indicate that the risk of GI side effects with low-dose ibuprofen appears comparable to paracetamol, when used in the management of common painful conditions, including headache (12). Meta analyses and systematic reviews also confirm that ibuprofen has the lowest relative risk of serious GI complications compared with other NSAIDs (11). The efficacy of NSAIDs may be explained by their effect on prostaglandin production. Prostaglandins are potent algogenic mediators that modulate multiple peripheral and central sites along the pain pathway
Box 2. Muscles that can refer pain to the head with active trigger points Upper trapezius Sternocleidomastoid Splenius capitis and cervicis Frontalis Temporalis Masseter Pterygoid splenius capitis and cervicis Suboccipital group Occipitalis Orbicularis oculi Zygomaticus Digastric Platysma Buccinator
ª 2015 John Wiley & Sons Ltd Int J Clin Pract, May 2015, 69 (Suppl. 182), 13–16
Perspective
Figure 1 Pressure point application to detect TTH trigger points. Adapted from Phillips and Froese (7)
Table 1 Drugs recommended for the treatment of
acute TTH (5) Drug
Dose
Ibuprofen Ketoprofen Aspirin Naproxen Diclofenac Paracetamol Caffeine combinations
200–800 mg 25 mg 500–1000 mg 375–550 mg 12.5–100 mg 1000 mg 65–200 mg
...........................
(13). This is particularly important in TTH, where mechanisms involving both peripheral and central sensitisation are thought to play a key role. By blocking the production of prostaglandins at both sites, NSAIDs promote a normalisation of the increased pain threshold observed in TTH (8). It is crucial to avoid frequent and excessive use of analgesics to prevent the development of medicationoveruse headache (MOH). Combination therapies containing caffeine are more likely to induce MOH
than simple analgesics or NSAIDs alone. Caffeinecontaining formulations are therefore reserved as second choice analgesic options for TTH and should not be used on more than 9 days/month (4,5). Triptans, muscle relaxants and opioids should be avoided altogether. In patients with chronic TTH, simple analgesics rarely have an effect (4) and prophylactic treatment may be considered, provided that MOH has been excluded. The first-line drug in this context is the tricyclic antidepressant amitriptyline (30–75 mg). Agents of second choice include mirtazapine and venlafaxine (4,5).
Summary and outlook Successful management of episodic TTH requires a multi-modal approach. Treatment can be improved, and the progression to chronic TTH prevented, by offering patients fast-acting formulations and treating early with the most effective drug at the appropriate dose. However, more work needs to be done to better understand the muscular mechanisms underlying
ª 2015 John Wiley & Sons Ltd Int J Clin Pract, May 2015, 69 (Suppl. 182), 13–16
15
16
Perspective
TTH and to develop more effective treatments based on this improved knowledge. Properly designed clinical trials are also required to identify the most effective drug options for treating TTH. In addition, professional education about headache disorders requires improvement to optimise the use of existing treatments and provide better outcomes for patients with TTH (5).
for activities related to headache, and received research support from charities, government and industry sources at various times. L. Bendtsen Department of Neurology, Danish Headache Center, Rigshospitalet, University of Copenhagen, Glostrup, Denmark
Disclosure LB has consulted and lectured for a number of pharmaceutical companies (including Reckitt Benckiser)
References 1 Steiner T, Paemeliere K, Jensen R et al. European principles of management of common headache disorders in primary care. J Headache Pain 2007; 8 (Suppl. 1): S3–47. 2 Lyngberg AC, Rasmussen BK, Jørgensen T, Jensen R. Prognosis of migraine and tension-type headache: a population-based follow-up study. Neurology 2005; 65: 580–5. 3 Simons DG, Travell JG, Simons LS, Travell & Simons’ Myofascial Pain and Dysfunction: The Trigger Point Manual. 1983. 4 Bendtsen L, Birk S, Kasch H et al. Danish Headache Society. Reference programme: diagnosis and treatment of headache disorders and facial pain. Danish Headache Society, 2nd Edition, 2012. J Headache Pain 2012; 13(Suppl. 1): S1–29. 5 Bendtsen L, Evers S, Linde M, Mitsikostas DD, Sandrini G. Schoenen J. EFNS guideline on the
6
7 8
9
10
treatment of tension-type headache - report of an EFNS task force. Eur J Neurol 2010; 17: 1318–25. WHO. Atlas of Headache Disorders and Resources in the World 2011. Geneva, Switzerland: WHO, 2011. Phillips C, Froese B. Cervical myofascial pain. Emedicine article 305937. September 2014. Torelli P, Jensen R, Olesen J. Physiotherapy for tension-type headache: a controlled study. Cephalalgia 2004; 24: 29–36. Fernandez-de-Las-Pe~ nas C, Alonso-Blanco C, Cuadrado ML, Miangolarra JC, Barriga FJ, Pareja JA. Are manual therapies effective in reducing pain from tension-type headache? A systematic review Clin J Pain 2006; 22: 278–85. Moore R, Derry S, Wiffen P, Straube S, Bendtsen L. Evidence for efficacy of acute treatment of episodic tension-type headache: methodological cri-
Correspondence to: Lars Bendtsen, Department of Neurology, Danish Headache Center, University of Copenhagen, Rigshospitalet, Glostrup DK-2600, Denmark Email: [email protected]
tique of randomised trials for oral treatments. Pain 2014; 155: 2220–8. Epub ahead of print. 11 Verhagen AP, Damen L, Berger M, Passchier J, Merlijn V, Koes B. Is any one analgesic superior for episodic tension-type headache? J Fam Pract 2006; 55: 1064–72. 12 Moore N, Van Ganse E, Le Parc J et al. The PAIN study: Paracetamol, Aspirin and Ibuprofen New tolerability study: a large scale, randomized clinical trial comparing the tolerability of aspirin, ibuprofen and paracetamol for short-term analgesia. Clin Drug Invest 1999; 18: 89–98. 13 Burian M, Geisslinger G. COX-dependent mechanisms involved in the antinociceptive action of NSAIDs at central and peripheral sites. Pharmacol Ther 2005; 107: 139–54.
Paper received June 2014, accepted November 2014
ª 2015 John Wiley & Sons Ltd Int J Clin Pract, May 2015, 69 (Suppl. 182), 13–16
Treatment guidelines: implications for community-based headache treatment Tension-type headache (TTH) is the most common form of headache in the community, affecting up to 80% of people from time to time (1). At least 10% of people experience episodic TTH on a frequent basis (up to 14 days per month) and the condition is chronic for 2– 3% (1). The outcome for patients with frequent episodic TTH is generally favourable, as shown in a study by Lyngberg et al. (2). When followed up after 12 years, 45% of patients had infrequent or no headaches (equivalent to remission), 39% still had frequent headache episodes and only 16% experienced chronic TTH. The mechanisms behind TTH are not fully understood because, despite the ubiquitous and disabling nature of this condition, there is a relative lack of research into primary headache disorders in general – and TTH in particular. Peripheral mechanisms seem to have an important role in episodic TTH, which is thought to develop as a result of pain referred from trigger points in pericranial muscles (3), coupled with the sensitisation of muscle nociceptors which causes increased pain sensitivity (4). In addition, in patients with frequent and chronic TTH, the central nervous system is hypersensitive to pain (4). The treatment of TTH ranges from nonpharmacologic therapies to the use of simple and combination analgesics. However, despite the high frequency of TTH and the associated burden on society, the scientific basis for many of the currently used treatment approaches (in particular nonpharmacological treatment) is limited. Several consensus-based treatment guidelines and reference publications are available, for example, from the European Federation of Neurological Societies (EFNS) (5), the Danish Headache Society (4) and the European Headache Federation (EHF) in collaboration with other organisations including the World Health Organisation (1). Effective management of headache disorders is further hampered by a lack of knowledge among healthcare professionals. Worldwide, only 4 h of formal undergraduate training are committed to headache disorders on average, making better professional education about headache disorders a key priority (6).
Non-pharmacological treatment approaches
Most headaches in patients with episodic TTH are mild-to-moderate, and nonpharmacological approaches (Box 1) have a key role in their management (5). European guidelines recommend that nondrug management of TTH should always be considered, despite the sparsity of scientific evidence for most widely used nonpharmacological approaches. (5) When a patient presents in primary care, just listening to the individual and taking their fears and concerns seriously can have a therapeutic effect. Thorough physical examination can also be helpful to reassure patients that their headache does not have a serious/life-threatening cause. Patients also benefit from information about the nature of the condition (5). This could include an explanation of how tension in the muscles of the head and neck acts as the source of a headache episode. Head and neck muscles are linked to peripheral nerves that trigger the characteristic, referred pain of headache. If prolonged, this can lead to a disturbance of the brain’s pain-processing mechanisms so that normally innocuous stimuli are perceived as painful (5) and the headaches become chronic. An important step towards empowering patients to self-manage their condition is the identification of trigger points and protective factors. For this purpose, it is useful if patients complete a headache diary; sample diaries and calendars can be downloaded from the website of the Danish Headache Society (www.dhos.dk). Common triggers of TTH include stress, irregular/inappropriate meals, caffeinated drinks, dehydration, lack of sleep, psycho-behavioural
Successful management of episodic TTH requires a multi-modal approach including use of nonpharmacological therapies and effective analgesics
Box 1. Non-pharmacological treatment of tension-type headache
• • • • • •
ª 2015 John Wiley & Sons Ltd Int J Clin Pract, May 2015, 69 (Suppl. 182), 13–16 doi: 10.1111/ijcp.12652
Physical examination and reassurance Inform the patient about disease mechanisms Minimise, to the extent possible, trigger factors, e.g. stress and unphysiological work postures Physiotherapy (daily exercise programme and posture correction) Biofeedback Stress and pain management
13
14
Perspective
problems, hormonal causes and reduced or inappropriate physical exercise. Other treatment programmes can be recommended based on the patient’s specific history, prior treatment and current diagnosis. Commonly used methods include electromyography biofeedback, relaxation techniques, stress management for preventing headache disorders and cognitive behavioural therapy. Relaxation training involves a range of affective, cognitive and behavioural techniques, such as breathing exercises and meditation. As with biofeedback, the aim is to enable the patient to recognise and control any tension in the head and neck muscles that arises during daily activities. In cognitive behavioural therapy, the patient learns to identify thoughts and beliefs that create stress and may result in headaches. Documented evidence of efficacy is only available for electromyography biofeedback, whereas data for the other methods remain inconclusive (5). Non-invasive physical therapy is also widely used to treat TTH, based on the premise that headache attacks originate in tender muscles of the head and neck (see Box 2 for muscles that can refer pain to the head with active trigger points). A snapping palpation of the muscle can reproduce the patient’s headache by activating local and referred pain pathways (see Figure 1 for the application of pressure points to detect trigger points) (7). Although potentially helpful in diagnosis, there is currently no data to support a role for the direct treatment of trigger points in the management of TTH, for example, using infiltration or local anaesthetics injected into the trigger point itself. Physical therapy includes general muscle treatment (massage, myofascial release, ice/heat and stretching) and release of specific muscle trigger points (trigger point pressure release and dry needling). It is also important to provide instruction on the improvement of posture and training in individual exercises that the patient can carry out at home. Physiotherapy can reduce the number of headache days in TTH by approximately 25% (8). Further research into the benefits of manual therapies is urgently needed (5,9).
Pharmacological treatment approaches The efficacy of pharmacological interventions to treat individual episodes of TTH is well established (5). Table 1 provides an overview of the drugs and doses recommended by the EFNS, based on current evidence. According to the EHF, although drug therapy has limited scope in TTH, it can prove effective in many patients (1). Symptomatic treatment with
over-the-counter analgesics is therefore recommended for episodic tension-type headache occurring on 2 or fewer days per week (1). The available evidence suggests that NSAIDs are more effective than paracetamol, while the latter may have a better gastrointestinal (GI) adverse event profile when compared with prescription-strength NSAIDs (5). In a large-scale meta-analysis evaluating the efficacy of oral agents for the acute treatment of episodic TTH, paracetamol (1000 mg), ibuprofen (400 mg) and ketoprofen (25 mg) were all shown to provide effective pain relief compared with placebo (10). However, it was noted that the available evidence for treatment efficacy in TTH is generally lacking when compared with the overall size of the clinical problem (10). The efficacy of NSAIDs in TTH has been further confirmed by a quantitative and qualitative analysis of 41 randomised, controlled trials (11). This systematic review showed that all types of NSAIDs were more effective than placebo against an acute episode of TTH, but found that no single NSAID was more effective than another (11). Among NSAIDs, ibuprofen has the most favourable GI tolerability profile and is therefore recommended by the EFNS as the drug of choice for TTH (4). Data from clinical trials indicate that the risk of GI side effects with low-dose ibuprofen appears comparable to paracetamol, when used in the management of common painful conditions, including headache (12). Meta analyses and systematic reviews also confirm that ibuprofen has the lowest relative risk of serious GI complications compared with other NSAIDs (11). The efficacy of NSAIDs may be explained by their effect on prostaglandin production. Prostaglandins are potent algogenic mediators that modulate multiple peripheral and central sites along the pain pathway
Box 2. Muscles that can refer pain to the head with active trigger points Upper trapezius Sternocleidomastoid Splenius capitis and cervicis Frontalis Temporalis Masseter Pterygoid splenius capitis and cervicis Suboccipital group Occipitalis Orbicularis oculi Zygomaticus Digastric Platysma Buccinator
ª 2015 John Wiley & Sons Ltd Int J Clin Pract, May 2015, 69 (Suppl. 182), 13–16
Perspective
Figure 1 Pressure point application to detect TTH trigger points. Adapted from Phillips and Froese (7)
Table 1 Drugs recommended for the treatment of
acute TTH (5) Drug
Dose
Ibuprofen Ketoprofen Aspirin Naproxen Diclofenac Paracetamol Caffeine combinations
200–800 mg 25 mg 500–1000 mg 375–550 mg 12.5–100 mg 1000 mg 65–200 mg
...........................
(13). This is particularly important in TTH, where mechanisms involving both peripheral and central sensitisation are thought to play a key role. By blocking the production of prostaglandins at both sites, NSAIDs promote a normalisation of the increased pain threshold observed in TTH (8). It is crucial to avoid frequent and excessive use of analgesics to prevent the development of medicationoveruse headache (MOH). Combination therapies containing caffeine are more likely to induce MOH
than simple analgesics or NSAIDs alone. Caffeinecontaining formulations are therefore reserved as second choice analgesic options for TTH and should not be used on more than 9 days/month (4,5). Triptans, muscle relaxants and opioids should be avoided altogether. In patients with chronic TTH, simple analgesics rarely have an effect (4) and prophylactic treatment may be considered, provided that MOH has been excluded. The first-line drug in this context is the tricyclic antidepressant amitriptyline (30–75 mg). Agents of second choice include mirtazapine and venlafaxine (4,5).
Summary and outlook Successful management of episodic TTH requires a multi-modal approach. Treatment can be improved, and the progression to chronic TTH prevented, by offering patients fast-acting formulations and treating early with the most effective drug at the appropriate dose. However, more work needs to be done to better understand the muscular mechanisms underlying
ª 2015 John Wiley & Sons Ltd Int J Clin Pract, May 2015, 69 (Suppl. 182), 13–16
15
16
Perspective
TTH and to develop more effective treatments based on this improved knowledge. Properly designed clinical trials are also required to identify the most effective drug options for treating TTH. In addition, professional education about headache disorders requires improvement to optimise the use of existing treatments and provide better outcomes for patients with TTH (5).
for activities related to headache, and received research support from charities, government and industry sources at various times. L. Bendtsen Department of Neurology, Danish Headache Center, Rigshospitalet, University of Copenhagen, Glostrup, Denmark
Disclosure LB has consulted and lectured for a number of pharmaceutical companies (including Reckitt Benckiser)
References 1 Steiner T, Paemeliere K, Jensen R et al. European principles of management of common headache disorders in primary care. J Headache Pain 2007; 8 (Suppl. 1): S3–47. 2 Lyngberg AC, Rasmussen BK, Jørgensen T, Jensen R. Prognosis of migraine and tension-type headache: a population-based follow-up study. Neurology 2005; 65: 580–5. 3 Simons DG, Travell JG, Simons LS, Travell & Simons’ Myofascial Pain and Dysfunction: The Trigger Point Manual. 1983. 4 Bendtsen L, Birk S, Kasch H et al. Danish Headache Society. Reference programme: diagnosis and treatment of headache disorders and facial pain. Danish Headache Society, 2nd Edition, 2012. J Headache Pain 2012; 13(Suppl. 1): S1–29. 5 Bendtsen L, Evers S, Linde M, Mitsikostas DD, Sandrini G. Schoenen J. EFNS guideline on the
6
7 8
9
10
treatment of tension-type headache - report of an EFNS task force. Eur J Neurol 2010; 17: 1318–25. WHO. Atlas of Headache Disorders and Resources in the World 2011. Geneva, Switzerland: WHO, 2011. Phillips C, Froese B. Cervical myofascial pain. Emedicine article 305937. September 2014. Torelli P, Jensen R, Olesen J. Physiotherapy for tension-type headache: a controlled study. Cephalalgia 2004; 24: 29–36. Fernandez-de-Las-Pe~ nas C, Alonso-Blanco C, Cuadrado ML, Miangolarra JC, Barriga FJ, Pareja JA. Are manual therapies effective in reducing pain from tension-type headache? A systematic review Clin J Pain 2006; 22: 278–85. Moore R, Derry S, Wiffen P, Straube S, Bendtsen L. Evidence for efficacy of acute treatment of episodic tension-type headache: methodological cri-
Correspondence to: Lars Bendtsen, Department of Neurology, Danish Headache Center, University of Copenhagen, Rigshospitalet, Glostrup DK-2600, Denmark Email: [email protected]
tique of randomised trials for oral treatments. Pain 2014; 155: 2220–8. Epub ahead of print. 11 Verhagen AP, Damen L, Berger M, Passchier J, Merlijn V, Koes B. Is any one analgesic superior for episodic tension-type headache? J Fam Pract 2006; 55: 1064–72. 12 Moore N, Van Ganse E, Le Parc J et al. The PAIN study: Paracetamol, Aspirin and Ibuprofen New tolerability study: a large scale, randomized clinical trial comparing the tolerability of aspirin, ibuprofen and paracetamol for short-term analgesia. Clin Drug Invest 1999; 18: 89–98. 13 Burian M, Geisslinger G. COX-dependent mechanisms involved in the antinociceptive action of NSAIDs at central and peripheral sites. Pharmacol Ther 2005; 107: 139–54.
Paper received June 2014, accepted November 2014
ª 2015 John Wiley & Sons Ltd Int J Clin Pract, May 2015, 69 (Suppl. 182), 13–16
