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BSc MPharm DipClinPharm
Highly Specialist Pharmacist for Pain Services
Southampton University Hospital NHS Trust
Neuropathic pain (NeP) can be defined as pain arising from a pathological or functional change in the peripheral or central nervous system. It is generally chronic and debilitating, with patients reporting a variety of abnormal pain sensations which may be ongoing or occur intermittently.
NeP is notoriously difficult to treat – in part due to the complex pathophysiological mechanisms involved but perhaps also as it is likely to be under-diagnosed, especially in patients who do not have a distinct neurological condition. Causes of NeP include diabetes (painful diabetic neuropathy), Varicella zoster (shingles) virus, amputation (phantom pain), cancer, HIV, multiple sclerosis, stroke, surgery and trauma and even drug therapy such as anti-virals used in HIV therapy.
Consequently, the prevalence of NeP in the community is likely to be high. Indeed, it is estimated that as many as half a million people are affected in the UK alone. It has been approximated that 1.7million people will be suffering from a major NeP disorder in five major European countries (France, Germany, Italy, Spain and UK) by 2012.
While the majority of patients with NeP will be predominantly treated by their family doctor, many will have time in hospital, even if is for the treatment of a seemingly unrelated condition. Hospital may well be where some patients’ NeP starts, perhaps following surgery, viral infection or stroke. We are increasingly aware of the link between poorly treated acute pain and its long-term manifestation as a persistent pain condition. Some patients describe neuropathic-type symptoms relatively quickly post-operatively, which, traditionally might have been dismissed as a by-product of the surgery that would resolve. Many units in the UK now use ‘neuropathic pain agents’ as part of their peri-operative regimens in order to reduce the risk of potential long-term problems.
Pathophysiology of neuropathic pain
The pain with which we are all most familiar is nociceptive pain – resulting from noxious stimuli. The basic process of pain transmission is divided into transduction, transmission, modulation and perception (see Figure 1).1
Transduction starts when nociceptors (free nerve endings of primary afferent neurons – see Table 1) are stimulated by a noxious stimulus – mechanical, thermal or chemical. This leads to depolarisation of the cell membrane, causing an action potential which triggers a ‘pain impulse’.
Transmission occurs at three sites in the pain process. The first is the site of transduction between the primary afferent neuron and the dorsal horn of the spinal cord; the second, between the spinal cord and brain stem; and the third is the transmission of pain impulses between the brain stem and thalamus, cortex and other higher centres of the brain. Excitatory neurotransmitters such as adenosine triphosphate (ATP), glutamate, bradykinin and substance P are involved in the transmission processes.
Modulation is where spinal cord transmission is changed or inhibited. It is the predominant operation of the descending pathways and occurs by either increasing inhibitory signalling or decreasing excitation of the ascending pathways.
Pain perception is the end result of the process and where pain becomes a multi-dimensional, conscious experience. Perception responses form in three main areas of the brain: the reticular system for autonomic and motor responses and the affective-motivational element of pain; the somatosensory cortex for perception and interpretation of the pain signals; and the limbic system forms emotional and behavioural responses to pain. Activation of the limbic system is linked to elements of pain conditions that are often difficult to treat such as mood changes, poor sleep and so on.
NeP can occur following injury or functional changes to peripheral or central nerves. Following nerve injury at a peripheral site there is accumulation of sodium channels within nociceptors and in the dorsal root ganglion. Changes are brought about by altered expression and increased distribution of sodium channels. The threshold for nociceptor depolarisation is lowered results in ectopic discharges and peripheral sensitisation.
Centrally, sensitisation can produce a ‘wind-up’ phenomenon. Up-regulation of NMDA receptors and increased levels of intracellular calcium result in a reduced depolarisation threshold of spinal horn neurons, in addition to increased magnitude and duration of response to stimuli. Induction of early gene expression can occur and contribute to plasticity and ‘pain memory’ that is associated with NeP. Loss of central descending inhibition is seen in NeP states and is associated with down-regulation of endogenous opioids, noradrenaline and serotonin, and reduced production of GABA.
Neuroplasticity (sprouting of A-delta fibres from the deep laminae of the dorsal horn into synapses within lamina I and II, where C-fibres terminate) is associated with NeP and may be partially responsible for allodynia.
Underlying processes of pain signalling are maintained in NeP but with the effective loss of control of their creation and inhibition, as described above. Symptoms such as paraesthesia and dysaesthesia, unique to NeP, are complex in their mechanism and do not respond well to ‘traditional’ analgesics such as opioids and non-steroidal anti-inflammatories.
Due to the conspicuous symptoms associated with NeP, it could be concluded that diagnosis is a reasonably simple affair. However, many patients with NeP go undiagnosed and consequently, under-treated for considerable periods of time. Patients can find it difficult to describe their pain or altered sensations and therefore, unless their family doctor specifically questions them for NeP, may not be forthcoming with the information that could be used to diagnose and treat them effectively.
There are several questionnaires available that can be used to assist in making a diagnosis of NeP. The Leeds Assessment of Neuropathic Signs and Symptoms Scale (LANSS)2 is considered the international standard assessment for NeP and is used in studies for pain assessment and monitoring of the effectiveness of treatments. More recently, PainDetect3 has become available. Questionnaires can be given to a patient suspected of having NeP to complete and return between appointments or while waiting to be called by the doctor. They can save unnecessary investigations and allow more time to discuss treatment options.
Many trials of medication used in neuropathic pain have concentrated on pain relief, rather than reduction of symptoms like hyperalgesia or dysaesthesia which many patients find more distressing. Unusually in medicine, the practitioner depends almost entirely on the patient’s own reporting of changes, good and bad, when making alterations to therapy. See Table 2 for a summary of the medication that can be used to treat neuropathic pain.
Non-opioid analgesics – Paracetamol forms the basis of any analgesic regimen. It has few side effects or interactions with other medication, making it suitable for chronic use in the majority of patients. Non-steroidal anti-inflammatory drugs (NSAIDs) perform well in trials but tend not to be used for NeP without a chronic inflammatory component, due to the risk of side effects such as ulcer and renal compromise. It is rare that paracetamol and/or NSAIDs are sufficient to manage NeP alone.
Antidepressants – Amitriptyline is the most frequently prescribed Tricyclic antidepressant (TCA) and ideally should be titrated from a low dose, eg, 10mg at 6–8pm to a usual maximum of 50–75mg. There is little difference between TCAs in terms of effectiveness but patients may try alternatives in order to minimise side-effects such as ‘hang-over effects’. There is limited evidence to support the use of SSRIs in NeP although in theory they should be effective and are known to be better tolerated than TCAs.
Anti-convulsants – Gabapentin and pregabalin are both licensed for NeP. Doses of gabapentin between 1800–3600mg daily in divided doses are commonly used. The dose of pregabalin is generally 150–600mg, again in divided doses. Both drugs can cause dizziness, drowsiness and weight gain although pregabalin is touted as being better tolerated. Bioavailability of pregabalin is higher than gabapentin (>90%4 versus 60%5 respectively). It would make sense then that pregabalin is effective at lower doses and has reduced potential for side effects. However, experience would deem that the drugs are differently tolerated rather than one being significantly superior to the other. Pregabalin may be titrated a little quicker than gabapentin (two weeks versus three to four weeks). This is potentially beneficial in NeP new in onset, such as phantom pain directly post-operatively, but it is less clear what benefit this has in patients with established NeP.
Opioids – Opioids tend to produce only a partial response in NeP and are rarely effective lone therapy. Evidence suggests that tramadol and oxycodone are the most effective if opioids are used. Tramadol has actions at both opioid and serotonin receptors, giving it properties similar to TCAs. Oxycodone is a relatively new opioid and has been included in trials for NeP unlike other established opioids. Methadone is used occasionally in NeP but should ideally be prescribed by a pain specialist. It may have advantages in reducing central sensitisation but it can be difficult to establish an effective dose and trial data to support its use is limited.
Cannabinoids – Sativex (delta-9-tetrahydrocannabinol and cannabidiol) is licensed in the UK for treating spasticity associated with multiple sclerosis. Research suggests that cannabinoids may provide future treatments and anecdotally, NeP patients using cannabis report good effects.
Topical creams – Capsaicin cream is licensed for NeP but application is needed four to five times a day for maximum benefit and it can cause burning pain at the application site, particularly if not used frequently enough. There is now a capsaicin plaster on the market (Qutenza) for painful peripheral neuropathy but is for specialist application only.
Topical anaesthetics – Versatis (Lidocaine plaster 5%) is licensed for treating post-herpetic neuralgia but its use in the UK has been extended to treating focal NeP of any origin. It is useful for patients with hyperalgesia, where the plaster provides protection from stimuli and also where burning pain is a symptom, due to the cool gel base used. Topical lidocaine enters the systemic circulation in insignificant levels, rendering the product virtually free of interactions and side-effects, other than a rare topical reaction.
Specialist treatments – Intravenous lidocaine and ketamine are occasionally used but should only be instituted by pain specialists in appropriate settings such as a hospital with Level 1 or 2 facilities. Older anti-epileptics like sodium valproate and phenytoin are occasionally used, as are corticosteroids which may be used to relieve compression neuropathies. Intrathecal injections and nerve blocks are options but relief is rarely long term and their appropriateness remains under debate among pain specialists.
Non-pharmacological interventions – Psychological techniques such as CBT tend to perform well in studies of patients with chronic pain of any cause. Outcomes can be beneficial in terms of providing the patient with coping strategies that can be utilised not just for pain management. It would appear that a combination of pharmacological, physical and psychological therapy, individualised to the patient is likely to be a good approach in the majority of cases. Transcutaneous electrical nerve stimulation performs well compared to placebo and may be useful particularly for patients reluctant to use, or unable to take, additional medication. Acupuncture is used in the management of NeP but systematic evidence to support its use is limited. Patient education is essential in the management of any chronic condition and NeP is no different. Certainly, concordance should be practiced in terms of making management decisions. The majority of specialist units in the UK would agree that they act to facilitate the patient in self-management of their condition rather than taking control of it for them. To this end, education plays a crucial role.
Referral to a specialist service – This should always be considered if there is any doubt about the diagnosis of NeP or if the patient has not responded well to treatment. Where there are restrictions placed upon the use of certain medications due to formulary and budgetary compliance, referral to a specialist unit may be necessary to access those therapies.
Use of guidelines for NeP – In England and Wales, the National Institute for Health and Clinical Excellence (NICE) released guidance on the management of NeP earlier this year.6 Local guidelines exist in many places that take into account community provision and restrictions on prescribing or access to specialist services. An example of such a guideline is given in Figure 2.7
NeP is difficult to manage and at the current time, there is no curative treatment. In addition, there is an emotional component to NeP and other chronic pain conditions and this must be dealt with in order to stand the best chance of managing the condition in the long term. Patients need to have explained at the outset, that the goal of any treatment is to modify the symptoms but that they might also need to consider non-medication methods of managing their pain and to some extent, their lifestyle if they are to make progress. Pharmacists are well placed to become involved in the symptomatic treatment of NeP by making medication recommendations and also in ensuring successful outcomes by managing side effects, drug interactions and encouraging compliance over time.
1. Bee LA, et al. Future Neurology 2007;2(6):661–71. Available online at: www.medscape.com/viewarticle/568704_9
2. Bennett MI. Pain 2001:92:147–57.
3. Freynhagen R, et al. Curr Med Res Opin 2006:22(10):1911–20.
4. Pfizer. SPC – Lyrica. Available online at: www.medicines.org.uk/EMC/medicine/14651/SPC/Lyrica+Capsules/ accessed September 2010.
5. Pfizer. SPC – Neurontin. Available online at: www.medicines.org.uk/EMC/medicine/17095/SPC/Neurontin+Capsules+and+Tablets/ accessed September 2010.
6. National Institute for Health and Clinical Excellence. CG96 Neuropathic pain – pharmacological management: full guideline. Available online at: http://guidance.nice.org.uk/CG96/Guidance
7. Davies E, et al. Clinical Pharmacist February 2010;S1–S2.