Pharmacotherapy of neuropathic back pain

Neuropathic pain in the back (BS) occurs due to damage to the nerve root. Most often this is observed with compression radiculopathy due to a herniated intervertebral disc or stenosis of the spinal canal. In typical cases, the clinical picture is characterized by symptoms that are traditionally described as radical (“radicular”) pains: acute “lumbago”, irradiation of pain along the nerve root, burning sensations, tingling in combination with symptoms of loss of sensitivity and a decrease in tendon reflexes. With the proven pain radicular syndrome, the standard use of traditional analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs) and muscle relaxants is not always effective, which negatively affects the rehabilitation process and the prognosis of the disease. In contrast to nonspecific BS, radicular pains are more likely to become chronic, substantially disadapt patients and reduce their quality of life. In many cases, when a herniated disc is found on the magnetic resonance imaging, unjustified (not according to indications) surgical treatment is performed, which often leads to the development of chronic pain within the framework of the syndrome of “unsuccessful operation on the spine”. Thus, the treatment of pain syndrome with radiculopathy seems rather complicated.

Mechanisms of pain

Representations of the mechanisms of pain in the lesion of the nerve root in recent years have changed significantly. Currently, several hypotheses of the formation of pain in compression radiculopathy are considered. Mechanical compression of the root leads to the development of foci of ectopic pathological impulses, excessive expression of potential-dependent sodium channels, peripheral sensitization. Against this background, central sensitization develops – increased sensitivity and excessive activity of sensory neurons of the posterior horn. Due to the lowering of the excitation threshold of these neurons, any non-bellicose peripheral stimulation can lead to the generation of painful impulses. With prolonged persistence of pain, the activity of descending antinociceptive influences decreases, which is interpreted as disinhibition. These mechanisms are characteristic of neuropathic pain and therefore pain with radiculopathy was called neuropathic. However, with radiculopathy, the source of pain may be damage to the nociceptors of the intervertebral disc itself. In addition, a certain role is played by the inflammatory process, when inflammatory mediators, locally acting on nerve endings in tissues, also participate in the generation of pain sensations. In this case, they talk about the nociceptive component of pain.

Thus, neuropathic (ectopic activity, sodium channel expression, central sensitization, disinhibition) and nociceptive mechanisms (nociceptor activation, inflammation) are involved in the formation of pain in radiculopathy. Of course, one should not forget about the significant role of psychogenic and social factors in the development and chronicle of pain syndrome, which is discussed in detail in the specialized literature. Structural injuries are likely to play the role of triggers, or trigger factors, and later chronic pain persists with the dominant role of neuropathic mechanisms of pathogenesis (neuroplasticity) and psychosocial factors, rather than morphological changes in the structures of the spine.

In view of these mechanisms of the pathogenesis of pain in radiculopathy, in recent years the rationale for differentiated rational pharmacotherapy is being increasingly discussed, which implies the use of drugs acting on the neuropathic, nociceptive and psychogenic components of pain. It is well known that nociceptive pains are successfully treatable with NSAIDs, whereas in neuropathic pain, anticonvulsants, antidepressants, opioids and local anesthetics are most effective. With a psychogenic component, psychotherapy and psychotropic drugs are appropriate. Thus, clarifying the representation of the neuropathic, nociceptive and psychogenic components, it is possible to compile an individual treatment regimen, combining drugs with different mechanisms of action.

Clinical evaluation and its features

It is clinically difficult to estimate the exact ratio and role of these components in radiculopathic pain syndrome. In the most general form, it can be said that the neuropathic component with pain in the lower back is characterized by “lumbago”, irradiation of pain along the spine, burning pain in the foot, Laceg’s symptom, whereas the nociceptive component is manifested by local aching, pulling, pulsating pain in the lumbosacral region without irradiation. Unfortunately, the existing additional diagnostic methods do not always allow us to specify the participation and role of this or that mechanism in the pathogenesis of pain. A good help in differentiating the clinical components of pain may be special questionnaires. In Russia, screening questionnaires Pain Detect and DN4 for neuropathic pain have been validated. With their help, you can quantify the probability of the presence of a neuropathic component in the BS.

Recent special studies show a high incidence of the neuropathic component in chronic BS. For example, in a study in the US in 213 patients with BS, radicular pain syndrome occurred in 28% of cases. In a population-based British study, among all respondents who reported an episode of BS within 1 year, 45.6% had signs of irradiating pain, numbness, and tingling in their legs. In the general population, the same signs were found in 17.8% of the interviewed people. Here it should be emphasized that not all cases of irradiating (reflected) pain can be classified as neuropathic. According to the definition, neuropathic pain is always due to an organic lesion (disease) of the somatosensory nervous system. Accordingly, pain with radiculopathy can be attributed to the neuropathic. However, it should be borne in mind that the reflected pain can occur not only with radicuulopathy, but also due to pathology of the ligamentous apparatus, epidural structures, muscles, facet joints, dysfunctions of the iliac-articular junction. For example, in a study in Saudi Arabia, where 100 patients with BS were tested using the LANSS questionnaire, 4196 patients showed signs of neuropathic pain. Most likely, in addition to patients with true radicular pains, patients with reflected pain (“non-neuropathic”), that is, not caused by damage to the nervous system. Thus, the data obtained during the questionnaire studies (using LANSS, DN4, PainDetect), should be treated with caution. It seems to us that the variability of the prevalence of the neuropathic component in BS is associated with the use of different clinical criteria for its evaluation. Nevertheless, according to the most extensive studies using the standard Pain Detect questionnaire and clinical analysis, the prevalence of the neuropathic component in chronic BS is 1.696 in the population.

Treatment

Traditionally, therapy of BS in most cases reduces to the use of pharmacological means and methods of non-drug treatment, such as massage, manual therapy, percutaneous electroneurostimulation, acupuncture, laser therapy, etc. Of invasive methods, drug blockades with novocaine, corticosteroids or botulinum toxin are widely used in various muscle points or joints. As for pharmacotherapy, there is a lot of practical experience in the use of simple analgesics, NSAIDs, muscle relaxants, lidocaine plates, antidepressants, anticonvulsants, opioids. However, the effectiveness of these methods in the therapy of the neuropathic BS is in most cases not obvious from the point of view of the principles of evidence-based medicine.

NSAIDs

It is well known that NSAIDs are highly effective in treating nociceptive pain. For the treatment of nonspecific BS they are first-choice drugs. However, with neuropathic pain, NSAIDs and paracetamol were ineffective and therefore not recommended for treatment and not included in international guidelines for the treatment of neuropathic pain. Only with a mixed type of pain (tunnel syndromes, radiculopathies, oncological pain), when both neuropathic and nociceptive components are present, they can be used to specifically target the nociceptive component, most often of an inflammatory nature. Thus, NSAIDs with BS can be used mainly for the treatment of nonspecific BS, when there is no damage to the nerve root, as well as in the complex therapy of radicular pain syndrome in combination with anticonvulsants, local anesthetics and antidepressants.

Antidepressants

Antidepressants have long been used in the treatment of chronic pain and, in particular, neuropathic pain. In general, tricyclic antidepressants (amitriptyline) and norepinephrine and serotonin reuptake inhibitors (duloxetine, venlafaxine, milnacipran) are used. This is due to their influence on the descending antinociceptive systems (noradrenergic, serotonergic), the function of ion channels, N-methyl-D-aspartate (NMDA) receptors. It is important to emphasize that the analgesic effect of these drugs does not depend on their antidepressant effect and comes a little earlier, which should be taken into account when prescribing and evaluating the effectiveness of treatment. It is recommended to always start with small doses (amitriptyline 12.5 mg per night, duloxetine 30 mg / day) and slowly increase, monitoring possible side reactions. Most authors point out that with chronic pain, antidepressants should be prescribed with ineffectiveness of anticonvulsants and local anesthetics.

A recently published meta-analysis of nine major studies casts doubt on the benefits of antidepressants compared with placebo in the therapy of chronic BS. For the sake of fairness, it should be noted that the analysis analyzed did not analyze the effect of antidepressants on nociceptive and neuropathic pain components.

Many researchers emphasize the low effectiveness of selective serotonin reuptake inhibitors (fluoxetine, paroxetine) in chronic BS. Therefore, these drugs are not included in the international recommendations for treatment.

Lidocaine

Work on the use of lidocaine patch in the BS is slightly. In general, they show a positive effect on both nociceptive and neuropathic pain components. In a non-randomized open-label study, W. White et al. (2003) shows a higher effectiveness of the combination of lidocaine patches and gabapentin than their independent use for 2 weeks of treatment of chronic BS. The general opinion of experts is reduced to the need for more studies with improved design.

Opioids

Opioid analgesics are used for high intensity pain. Meta-analyzes show that they are equally effective in treating both nociceptive and neuropathic pain components. Serious adverse reactions are a major problem in the use of these drugs. In general, tramadol is more commonly used, which has shown high efficiency in the treatment of both nociceptive and neuropathic components of pain when taken from 200 to 400 mg / day.

Anticonvulsants

Among anticonvulsants, the most recognized drugs for the treatment of neuropathic pain are gabapentin and pregabalin. The mechanism of their action is associated with the influence on the central mechanisms of pain: a decrease in central sensitization, an improvement in the neurotransmitter balance in the direction of intensifying anti-GABAergic effects and reduction of the effects of glutamate, the main neurotransmitter of pain.

We conducted a study on the use of gabapentin in the treatment of BS in 18 patients with chronic radiculopathy. Patients received gabapentin for 3 months, starting at 300 mg / day, with a gradual titration of up to 2,400 mg / day. The study showed the overall effectiveness of gabapentin in the treatment of chronic BS. However, the clinical effect was not observed in all patients equally. The best results were obtained in patients with a typical picture of radicular pain: “lumbago”, irradiation by the root type (ie, neuropathic by mechanism). Less pronounced improvement was noted in patients with bilateral pain, without irradiation and “lumbago” (ie nociceptive by mechanism). Similar data were obtained in a McCleane study in 80 patients with chronic lower back pain without a neuropathic component who reported an unreliable decrease in the score from the visual analogue scale at the end of the course of therapy.

The purpose of our other study was to evaluate the pain syndrome in chronic radiculopathy in terms of the severity of the neuropathic pain component and evaluate the clinical efficacy of gabapentin for targeted therapy of this component. A group of patients comprised 37 patients with chronic lumbosacral radiculopathy. Treatment with gabapentin was carried out at a dose of 1800 mg / day (600 mg 3 times a day) for 6 weeks with preliminary titration. In general, the treatment was more effective in patients with initially higher scores according to the DN4 and PainDETECT questionnaires, i.e. with a pronounced neuropathic component. The results of the work showed the high effectiveness of gabapentin in relation to the reduction of the neuropathic pain component. This, on the one hand, indicates that in the formation of pain in radiculopathy, the neuropathic component plays an important role, and on the other hand indicates the possibility of effective exposure to this component with gabapentin.

Pregabalin, possessing linear pharmacokinetics, has an advantage over gabapentin with respect to the rapidity of the onset of the effect. Special studies have studied the efficacy of pregabalin in neuropathic BS. It has been shown that pregabalin is more effective when used in combination with NSAIDs or opioid analgesics than as monotherapy.

The topiramate at radiculopathy study has shown its efficiency, but due to frequent side effects (nausea, sedation, prarestezii, amnesia), it is considered only as a means of selecting a second-order and is indicated in patients subject to its good tolerability.

Combination Therapy

The main principle of pharmacotherapy of neuropathic pain is the principle of rational polypharmacy. Today, to solve the problem of this type of pain, using only one drug or one class of drugs, practically fails. But the choice of these or other pharmacological means of treatment should be based on the knowledge of different pathophysiological mechanisms and their participation in the formation of pain in a particular patient. As noted, the pharmacotherapy of patients with radicular pain should be combined, taking into account the contribution of nociceptive, neuropathic and psychogenic component, as they are all from the specific gravity are present in patients with chronic pain.

Unfortunately, so far few randomized controlled trials for combination therapy have been conducted. In this respect, a placebo-controlled study on the simultaneous use of celecoxib and pregabalin in 36 patients with chronic BS is indicative. One group took only tselebrex, the other – pregabalin, the third – tseledreks and pregabalin at the same time. A significantly higher efficacy of combination therapy is shown than monotherapy with these drugs, with the same tolerability. At the same time, the dose of each drug with combined therapy was on average lower than with monotherapy.

In a study of pregabalin in combination with oxycodone participated 409 patients with radicular BS treated for 3 months starting with a low dose and gradually increase to a level of optimal pain relief and drug tolerability. In terms of the effect on pain and quality of life, the combination of pregabalin and oxycodone was significantly more effective than monotherapy with these drugs. With combined therapy, the amount of oxycodone was 22% less than with monotherapy. In the group on combined therapy, fewer cases of discontinuation of treatment due to side effects were noted. Constipation was the most frequent side effect.

In another study in patients with chronic BS, pregabalin was studied in combination with buprenorphine in the form of a transdermal therapeutic system. A significantly higher efficacy of combination therapy compared with buprenorphine monotherapy is shown.

The combination of the standard dose of paracetamol and tramadol tablet 1 – 37.5 mgtramadola, 325 mg of paracetamol (in Russian analog of such preparation is Zaldiar) was studied in chronic BS in two studies. In these studies, a significant decrease in the intensity of the pain syndrome was demonstrated. In a study of the simultaneous use of paracetamol and oxycodone in chronic pain in the joints and back, the high efficacy of such a combination was shown, but there was no evidence of the benefits of this combination with respect to the neuropathic component of pain.

Using morphine with nortriptylin, 61 patients with radicular pain did not receive a statistically significant effect on pain, and side effects were reported in 89% of cases.

These results once again underline the thesis that radicular pain is mixed and in therapy, drugs acting on different mechanisms of pain should be used simultaneously. Such studies indicate the importance and need for further research on combined therapy for neuropathic pain. For example, it is already obvious today that monotherapy with pregabalin is significantly inferior in effectiveness to its combinations with tselrebeks, oxycodone or buprenorphine.

Conclusion

Pharmacotherapy of patients with radicular pain should be combined taking into account the contribution of nociceptive, neuropathic and psychogenic components, since all of them with a certain specific gravity are present in these patients. For the selection of specific drugs for the treatment of pain, it is important to know the pathophysiological mechanisms. Diagnosis of only structural changes in the spine is inadequate for the choice of therapy. Along with a very important assessment of all the changes occurring in the spine, it is necessary to take into account that chronic pain is an independent disease with its peripheral and central mechanisms of pathogenesis. The clinician should approach the pharmacotherapy of the BS through an understanding of such important peripheral mechanisms as neurogenic inflammation, peripheral sensitization, expression of the sodium channels of neurons, and ectopic activity. It is also necessary to evaluate the effect of these peripheral changes on processes in the central nervous system: activation of NMDA receptors, the phenomenon of inflation, central sensitization, secondary hyperalgesia, disorders in descending suprasegmentary pain control (disinhibition).

Thus, in the presence of a neuropathic component, special drugs should be preferred for the treatment of neuropathic pain (gabapentin, pregabalin, lidocaine, antidepressants). However, it is obvious that longitudinal control studies on the treatment of the neuropathic component of the BS should be continued. Of course, we will wait for the results of new control studies on the use of mono- and polypharmacotherapy in the treatment of neuropathic BS, on the basis of which more precise treatment recommendations based on the principles of evidence-based medicine will be developed.

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