The Role of Antineuropathic Drugs in the Treatment of Chronic Low Back Pain

Chronic pain is a public health problem affecting 20-30% of the population in Western countries (Dansie & Turk, 2013), with moderate to severe chronic pain found in 19% of the population. It is an important healthcare problem with a significant impact in all the bio-psycho-social components of life and a burden for the society. Its management seems to be defying, with 40% of the patients dissatisfied with the effect of treatment (Breivik et al., 2006; Fayaz et al., 2016).

One of the most common chronic pain conditions is low back pain (LBP).

LBP is defined as pain and discomfort between the costal margins and the inferior gluteal folds, with or without referred leg pain. It is considered to be chronic after 12 weeks of persistent pain (Airaksinen et al., 2006).

Chronic LBP comprises nociceptive and neuropathic components, but the neuropathic component appears to be underrecognised and, consequently, undertreated (Baron et al., 2016). LBP is the most common cause of years lived with disability and the sixth leading cause of disability-adjusted life-years (Murray et al.

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, 2012).

It's important to retain that patients with neuropathic LBP have an increased severity of medical comorbidities, reduced quality of life and higher healthcare costs than non-neuropathic LBP. This is an important point, since 90% of patients with chronic LBP have a neuropathic component (Mehra et al., 2012).

LPB is associated with comorbid conditions; the most common being depression, panic, anxiety and sleep disorders (Baron et al., 2016). This can make it difficult to find the most adapted pharmacology to each patient, with 40% of patients recognised as not having clinically meaningful analgesia with oral pharmacotherapies.

Patients should receive appropriate pain treatment based on a careful consideration of the benefits and risks of treatment options (Attal et al., 2011; CDC, 2016).

Chronic LBP is a multifactorial disease with an impact on multiple systems, so practitioners need to be aware of that when choosing the intervention. Along with non-pharmacological interventions, pharmacology has an important role in pain management. To manage chronic LBP, the existing pharmacological agents are paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, anti- neuropathic drugs and topical treatments. Paracetamol and NSAIDs have effects in nociceptive pain, but no effect in neuropathic pain. Treatments with opioids should not be considered at first due to concerns regarding tolerability and dependence (Baron et al, 2016; Fayaz et al, 2016).

The next table presents the available pharmacology used in treatment of neuropathic pain and chronic LPB.

The aim of anti-neuropathic medicines is to reduce nerve activity and pain hypersensitivity. They take action in neuropathic pain but not in nociceptive or inflammatory pain. Anti-neuropathic pain medicines have an analgesic effect mediated by their action on descending modulatory and inhibitory controls and include antidepressants (effects on noradrenergic noradrenergic and serotoninergic neurotransmission) and anticonvulsants (acting at calcium channels) (Colocca et al., 2017; Fornasari 2017; Pain health, 2016).

Antidepressants

In chronic pain and depression, hyperalgesia can result from central sensitisation as a consequence of plastic changes in the nervous system (Latremoliere and Woolf, 2009). One of the hypotheses is that depression and somatic pain symptoms may arise from a common neurobiological dysfunction of the serotonergic and noradrenergic neurons in both ascending and descending pathways from the basal ganglia. This hypothesis supposes that depression and chronic pain produce common negative neuroplastic changes in the CNS (Bohren et al, 2013; Nekovarova et al., 2014).

There is a close association between chronic pain and depression, with 43.4% of patients with major depression complaining about chronic pain symptoms. Consequently, several patients with chronic pain were prescribed with antidepressants. Surviving oncological patients using antidepressants reported lower pain in chronic pain intensity than oncological patients not taking antidepressants. Another interesting finding is that even though it is a small sample (10 in each group), 7 out of ten patients survived from patients treated with antidepressants, while only 3 survived in the group of patients who were not treated with antidepressants, but further research is needed to confirm that correlation (Delgado 2006).

The positive impact of antidepressants would result in a reduction of the pathological processes and in the amelioration of symptoms. They are also linked to an improvement in the quality of life of treated patients (Nekovarova et al., 2014).

Tricyclic antidepressants (TCAs) have become a standard treatment of chronic and neuropathic pain. They appear to produce moderate symptom reductions for patients with chronic LBP, regardless of the depression status. They have pleiotropic effects and are not selective, which appears to contribute to their efficacy. However, they are also responsible for many adverse drug reactions, which limit their use (in particular anticholinergic effects) (Richelson 2001).

The SSRI fluoxetine presents anti-inflammatory properties (Yaron et al., 1999) but does not appear to be particularly effective in the treatment of LBP when used in isolation (Staiger et al., 2003).

Recent data suggests that SNRIs may be as effective as the TCAs in relieving pain, without the anticholinergic effects and with more effectivity than SSRIs. When compared to placebo in patients with major depression, duloxetine significantly reduced painful physical symptoms, such as back pain, in addition to reducing depression scores (Ball et al., 2012; Delgado, 2006).

The pain-relieving activity of antidepressants was independent of whether the patients were suffering from comorbid depression. When comparing the pain-relieving effects of dual-acting reuptake inhibitors, SSRIs and noradrenaline reuptake inhibitors (NRI), the dual- action antidepressants were more active than NRIs, which were more active than SSRIs. Dual-action antidepressants may become the new standard of medicine for chronic pain both associated and not associated with depression (Delgado 2006; Sindrup et al., 2003; Urquhart et al., 2008).

Anticonvulsants/antiepileptics

These medications were first used to control epileptic seizures and can also help reduce nerve pain and are often a first line treatment option. Antiepileptic drugs are used in the management of LBP, since it appears that the neurochemical mechanisms of epilepsy and neuropathic pain have a common physiology (Ryder & Stannard, 2005).

Antiepileptic drugs are widely used in pain clinics since 1940 and work in different ways, all with an effect on pain (Backonja 2002). An analgesic effect is related to a decrease in central sensitisation by binding to the a28 subunit of calcium voltage-gated channels (Colloca et al., 2017).

Gabapentin (no relation with GABAergic systems) appears to have an inhibitory action at voltage-gated calcium channels where it blocks the a28 subunit, decreasing central sensitisation. Its efficacy is comparable with older agents but with a less side-effect profile, lack of interactions and straightforward pharmacokinetics (Backonja 2002; Rogawski & Loscher 2004).

Pregabalin also acts on the ad subunit of voltage-gated calcium channels, although its pharmacokinetic properties are different from gabapentin. It has analgesic, anxiolytic and anticonvulsant activity, with relief from pain and a decrease in sleep interference. It efficacy and side effect profile is similar to gabapentin, but it is easier to titrate (Sabatowski, Galvez & Cherry (2004).

The side-effects of the antiepileptic drugs are usually those affecting the CNS, gastrointestinal and haematological systems and interaction with other drugs (Ryder & Stannard, 2005).

Conclusion

Chronic pain should be recognised as a disease in itself and not just a symptom. The goal of the treatment of chronic LBP is to reduce pain, maintain function and prevent future exacerbation. As a multidimensional problem, low back pain treatment should be selected with a multidimensional approach, with both physical and psychological intervention (Baron R, 2016).

The use of several drugs of different classes has theoretical support in the management of LBP (Ryder & Stannard 2005). Globally, anti-neuropathic drugs have good results in monotherapy or combination therapy (with drugs with different mechanisms of action), and it represents a rational approach. The fact that they are not addictive and tolerable allows the patients to take them safely for prolonged periods of time. Moreover, the doses necessary to improve pain are often lower than those used to treat depression (Ryder & Stannard 2005).

Further research of pharmacology in chronic LBP with well-designed studies is required to confirm all the hypotheses mentioned in this essay, but the anti- neuropathic drugs seem to have an important influence in clinical practice with reduction of the symptoms both for pain and depression.

There is strong recommendation for their use and proposal as first line treatment TCAs, SNRIs, pregabalin and gabapentin (Finnerup et al., 2015). In the interest of the patients, an effort to know and use the best pharmacological recommendations and guidelines by the clinician is suggested, allowing the choice of the most adapted pharmacological treatment for each patient and the reduction of the associated costs of unadapted prescriptions.