Description of the condition

Neuropathic pain is a consequence of a pathological maladaptive response of the nervous system to 'damage' from a wide variety of potential causes (Colloca 2017). It is characterised by pain in the absence of a noxious stimulus, or where minor or moderate nociceptive stimuli evoke exaggerated levels of pain. Neuropathic pain may be spontaneous (continuous or paroxysmal) in its temporal characteristics or be evoked by sensory stimuli (dynamic mechanical allodynia where pain is evoked by light touch of the skin).

Neuropathic pain is heterogeneous in aetiology, pathophysiology, and clinical appearance. The 2011 International Association for the Study of Pain definition of neuropathic pain is "pain caused by a lesion or disease of the somatosensory system" (Jensen 2011), and is based on a definition agreed at an earlier consensus meeting (Treede 2008). Neuropathic pain is associated with a variety of sensory loss (numbness) and sensory gain (allodynia) clinical phenomena, the exact pattern of which varies between people and disease, perhaps reflecting different pain mechanisms operating in an individual person and, therefore, potentially predictive of response to treatment (Demant 2014; Helfert 2015; von Hehn 2012). A new approach of subgrouping people with peripheral neuropathic pain of different aetiologies according to intrinsic sensory profiles has generated three profiles that may be related to pathophysiological mechanisms and may be useful in clinical trial design to enrich the study population for treatment responders (Baron 2017).

Preclinical research hypothesises a bewildering array of possible pain mechanisms that may operate in people with neuropathic pain, which largely reflect pathophysiological responses in both the central and peripheral nervous systems, including neuronal interactions with immune cells (Baron 2012; Calvo 2012; von Hehn 2012). Overall, the benefits of drugs for neuropathic pain treatments, even the most effective, are modest (Finnerup 2015; Moore 2013a), and a robust classification of neuropathic pain is not yet available (Finnerup 2013).

Neuropathic pain is usually divided according to the cause of nerve injury. There may be many causes, but some common causes of neuropathic pain include diabetes (painful diabetic neuropathy (PDN)), shingles (postherpetic neuralgia (PHN)), amputation (stump and phantom limb pain), neuropathic pain after surgery or trauma, stroke or spinal cord injury, trigeminal neuralgia, and HIV infection. Sometimes the cause is unknown.

Many people with neuropathic pain conditions are significantly disabled with moderate or severe pain for many years. Chronic pain conditions comprised five of the 11 top‐ranking conditions for years lived with disability in 2010 (Vos 2012), and are responsible for considerable loss of quality of life and employment, and increased healthcare costs (Moore 2014a). One US study found the healthcare costs were three‐fold higher for people with neuropathic pain than matched controls (Berger 2004). A UK study and a German study showed a two‐ to three‐fold higher level of use of healthcare services in people with neuropathic pain than people without (Berger 2009; Berger 2012). For PHN, for example, studies demonstrated large loss of quality of life and substantial costs (Scott 2006; van Hoek 2009).

In systematic reviews, the overall prevalence of neuropathic pain in the general population is reported to be between 7% and 10% (van Hecke 2014), and about 7% in a systematic review of studies published since 2000 (Moore 2014a). In individual countries, prevalence rates have been reported as 3.3% in Austria (Gustorff 2008), 6.9% in France (Bouhassira 2008), and up to 8% in the UK (Torrance 2006). In a community study of recent joint pain, features of neuropathic pain were common and were present in over half of those people reporting pain of at least moderate severity (Soni 2013). Some forms of neuropathic pain, such as PDN and postsurgical chronic pain (which is often neuropathic in origin), are increasing (Hall 2008). The prevalence of PHN is likely to fall if vaccination against the herpes virus becomes widespread.

Estimates of incidence vary between individual studies for particular origins of neuropathic pain, often because of small numbers of cases. In primary care in the UK, between 2002 and 2005, the incidences (per 100,000 person‐years' observation) were 28 (95% confidence interval (CI) 27 to 30) for PHN, 27 (95% CI 26 to 29) for trigeminal neuralgia, 0.8 (95% CI 0.6 to 1.1) for phantom limb pain, and 21 (95% CI 20 to 22) for PDN (Hall 2008). Other studies have estimated an incidence of 4 in 100,000 per year for trigeminal neuralgia (Katusic 1991; Rappaport 1994), and 12.6 per 100,000 person‐years for trigeminal neuralgia and 3.9 per 100,000 person‐years for PHN in a study of facial pain in the Netherlands (Koopman 2009). One systematic review of chronic pain demonstrated that some neuropathic pain conditions, such as PDN, can be more common than other neuropathic pain conditions, with prevalence rates up to 400 per 100,000 person‐years (McQuay 2007).

Neuropathic pain is difficult to treat effectively, with only a minority of people experiencing a clinically relevant benefit from any one intervention (Kalso 2013; Moore 2013a). A multidisciplinary approach is now advocated, combining pharmacological interventions with physical or cognitive (or both) interventions. The evidence of benefit from interventional management is very weak, or non‐existent (Dworkin 2013). Conventional analgesics such as paracetamol and nonsteroidal anti‐inflammatory drugs (NSAID) are not thought not to be effective, but without evidence to support or refute that view (Moore 2015a; Wiffen 2016). Some people may derive some benefit from a topical lidocaine patch or low‐concentration topical capsaicin, although evidence about benefits is uncertain (Derry 2012; Derry 2014). High‐concentration topical capsaicin may benefit some people with PHN (Derry 2017). Treatment is often by so‐called 'adjuvant analgesics' (pain modulators) such as antidepressants (duloxetine and amitriptyline; Lunn 2014; Moore 2014b; Moore 2015b; Sultan 2008), or antiepileptic drugs (gabapentin or pregabalin; Moore 2009; Moore 2014c; Wiffen 2013). Evidence for efficacy of opioids is inconclusive (Derry 2016; Gaskell 2016; Stannard 2016; Wiffen 2015).

The proportion of people who achieve worthwhile pain relief (typically at least 50% pain intensity reduction; Moore 2013b) is small, generally only 10% to 25% more than with placebo, with numbers needed to treat for an additional beneficial outcome (NNT) usually between 4 and 10 (Kalso 2013; Moore 2013a). Neuropathic pain is not particularly different from other chronic pain conditions in that only a small proportion of trial participants have a good response to treatment (Moore 2013a).

The current National Institute for Health and Care Excellence (NICE) guidance for the pharmacological management of neuropathic pain suggests offering a choice of amitriptyline, duloxetine, gabapentin, or pregabalin as initial treatment for neuropathic pain (with the exception of trigeminal neuralgia), with switching if the first, second, or third drugs tried are not effective or not tolerated (NICE 2013). This concurs with other guidance (Finnerup 2015).

Description of the intervention

Morphine in one form or another has been available for millennia, and appeared in Pliny's Historia Naturalis (AD 77) as opium, the resin derived from poppy sap. Morphine was extracted from opium in 1803 and named as such by Sertürner, a German pharmacist, in 1817 (Rey 1993). Oral morphine was first recommended in England for the treatment of cancer pain in the 1950s. This was often in the form of the so‐called 'Brompton cocktail' containing cocaine and alcohol in addition to morphine or diamorphine. Treatment moved towards oral morphine alone as morphine demonstrated effective pain relief without the adverse effects linked to the 'cocktail'.

Following the publication of World Health Organization (WHO) guidelines in the mid‐1980s, the oral administration of aqueous morphine solution every four hours by the clock became commonplace for moderate to severe cancer pain (WHO 1986). Morphine in a modified‐release tablet was first marketed around the same time, allowing the dosage interval to be extended to 12 hours.

Morphine, usually as the sulphate or hydrochloride salt, is available in four oral formulations: an elixir or solution of morphine in various concentrations; an immediate‐release tablet; a number of different preparations of modified‐release tablets or capsules; and modified‐release suspensions. A table showing the brand names of morphine preparations is provided in Appendix 2. Modified‐release tablets are available in both 12‐hour and 24‐hour release patterns and should be swallowed whole. They have lower maximum plasma concentrations and longer time to maximum concentration than equal doses of immediate‐release formulations (Collins 1998).

The wide range of formulations and dosages allows great flexibility (Grahame‐Smith 2002). Potent opioid analgesics are indicated for the relief of pain in malignant disease and often have the additional very useful actions of relieving anxiety, producing drowsiness, and allowing sleep (Grahame‐Smith 2002). However, all opioid analgesics have the potential to produce adverse effects including respiratory depression, nausea and vomiting, constipation, urinary retention, cognitive impairment, and itching. During chronic opioid therapy, progressively higher doses may be required to sustain the analgesic effect (tolerance) and people can be at risk of opioid withdrawal syndrome upon sudden cessation of the opioid or administration of an antagonist (physiological dependence).

Morphine is also available for intravenous, intramuscular, or subcutaneous injection, and is used for injection around the spinal cord or within the brain in some circumstances. Sublingual, buccal, and rectal routes of administration of morphine are sometimes used. None of these ways of administering morphine is likely to be used for neuropathic pain, but we did not exclude them from this review.

How the intervention might work

Opioids such as morphine bind to specific opioid receptors in the nervous system and other tissues; there are three principal classes of receptors (mu, kappa, and delta) although others have been suggested, and subtypes of receptors are considered to exist. Binding of opioid agonists such as morphine to receptors brings about complex cellular changes that, for the most part, acutely inhibit injury‐induced activation of nociceptive pathways. The outcomes include decreased perception of pain, decreased reaction to pain, and increased pain tolerance. As a result, people treated with morphine report decreased pain and decreased reaction to tissue injury. However, paradoxical excitatory effects of morphine administration have been observed in some nociceptive neurons and in the brain, particularly after prolonged administration.

Why it is important to do this review

One UK survey found that weak and strong opioids were used frequently for treating neuropathic pain (Hall 2013). Morphine (a strong opioid) has long been considered as the preferred choice of opioid. It is widely, though still not universally, available across the world, is comparatively inexpensive, and is effective orally. It is listed in the WHO Essential Medicines List (WHO 2011). Since the early‐2000s, a marked increase in prescribing of opioids for non‐cancer pain in general, despite a relatively modest evidence base, has in some countries led to widespread diversion with consequent abuse, misuse, and mortality. Concurrently, suspicion has arisen that opioid‐induced hyperalgesia, together with tolerance to the analgesic effects of opioids, may in reality result in a lesser degree of benefit for opioids in neuropathic pain than previously assumed.

The standards used to assess evidence in chronic pain trials have evolved substantially in recent years, with particular attention being paid to trial duration, withdrawals, and statistical imputation following withdrawal, all of which can substantially alter estimates of efficacy. The most important change is the move from using mean pain scores, or mean change in pain scores, to the number of people who have a large decrease in pain (by at least 50%) and who continue in treatment, ideally in trials of 8 to 12 weeks' duration or longer. Pain intensity reduction of 50% or more correlates with improvements in comorbid symptoms, function, and quality of life. These standards are set out in the PaPaS Author and Referee Guidance for pain studies of the Cochrane Pain, Palliative and Supportive Care Group (PaPaS 2012).

This Cochrane Review assesses the evidence using methods that make both statistical and clinical sense, and uses developing criteria for what constitutes reliable evidence in chronic pain (Moore 2010a). Trials included and analysed meet a minimum of reporting quality (blinding, randomisation), validity (duration, dose and timing, diagnosis, outcomes, etc.), and size (ideally at least 500 participants in a comparison in which the number needed to treat is 4 or above; Moore 1998). This approach sets high standards for the demonstration of efficacy and marks a departure from how reviews were conducted previously.

Taking this newer, more rigorous approach is particularly important for opioids in chronic non‐cancer pain. Opioids in clinical trials in non‐cancer pain are associated with very high withdrawal rates of up to 60% over about 12 weeks (Moore 2010b). Many withdrawals occur within the first few weeks, when patients experience pain relief but cannot tolerate the drug. The common practice of using the last observed results carried forward to the end of the trial many weeks later (last observation carried forward (LOCF)) can, therefore, produce results based largely on people no longer in the trial, and who in clinical practice could not achieve pain relief because they could not take the tablets. The newer standards, outlined in Appendix 1, would not allow this LOCF effect and may produce very different results. For example, one large analysis of pooled data from trials in osteoarthritis and chronic low back pain conducted over about 12 weeks judged oxycodone effective, but an analysis of the same data using the new clinically meaningful standards showed it to be significantly worse than placebo (Lange 2010).

One previous Cochrane Review demonstrated the limitations of our knowledge about opioids in neuropathic pain, except in short duration studies of 24 hours or less (McNicol 2013). These limitations were confirmed by more recent reviews specific to particular opioids (Derry 2016; Gaskell 2016; Stannard 2016; Wiffen 2015). A review specific to morphine is timely, given its wide availability and use, and distinctive patterns of metabolism to an array of byproducts some of which may worsen, and others improve, pain (Ball 1985; Faura 1996; Hand 1987).