Chronická bolest dolních zad: současné typy farmakoterapie a nový biologický přístup

Chronická bolest dolních zad: současné typy farmakoterapie a nový biologický přístup

Syndrom chronické bolesti dolní části zad (CLBP) představuje celosvětově jednu z hlavních příčin dlouhodobého zdravotního postižení. Prevalence CLBP významně roste s věkem. Problém dosavadní farmakoterapie CLBP spočívá v nežádoucích účincích mnoha tradičně používaných léků. Hledají se proto nové, bezpečnější metody léčby. Mezi inovativní možnosti terapie CLBP patří injekce obsahující kolagen. V mezinárodním časopise Current Medicinal Chemistry byl publikován na toto téma článek Chronic low back pain: current pharmacotherapeutic therapies and a new biological approach. V autorském kolektivu, vedeném ředitelem Revmatologického ústavu v Praze prof. MUDr. Karlem Pavelkou, DrSc., jsou zastoupeni i autoři z InPharm Clinic a Edukafarmu. Přinášíme článek v původním anglickém znění. 

Chronic Low Back Pain: Current Pharmacotherapeutic Therapies and New Biological Approach

  1. K. Pavelka1, H. Jarosova1, O. Sleglova1, R. Svobodova1, M. Votavova1, L. Milani2, Z. Prochazka3, L. Kotlarova3, P.Kostiuk3 , J. Sliva4, A. M. Meroni5 

  Institute of Rheumatology, Prague, Czech Republic;

 2 University Sapienza, Rome and Univerzity of Siena, Italy;

 3 Edukafarm, Prague, Czech Republic;

 4 3rd Faculty of Medicine, Charles University, Prague, Czech Republic;

 5 Department of Orthopedics and Traumatology, Niguarda Hospital, Milano, Italy 


Abstract: 
The syndrome of chronic low back pain (CLBP) represents one of the leading causes of long-term disability worldwide. The prevalence of CLBP rises significantly in relation to increasing average of life expectancy. CLBP arises by chronification of acute low back pain. There are many factors that contribute to the emergency of CLBP; frequent etiopathogenetic factors include e.g. a functional blockage of intervertebral joints. The treatment of CLBP has a complex character. An important part of treatment consists of pharmacotherapy of pain, under which several groups of drugs are being used. The problem lies in the side effects of many of these traditionally used substances. Therefore, new and safer methods of treatments are being searched. Innovative option of pharmacology of CLBP represents injections containing collagen, which can be combined with the traditionally used drugs, thus helping to reduce their dosage and to increase the overall safety of therapy of CLBP. 


Keywords: Chronic low back pain, chronic pain management, pharmacotherapy of chronic pain, safe therapy of pain, pain control, collagen-containing injections.  


INTRODUCTION

Low back pain (LBP) is the most common disease of the musculoskeletal system, which affects the adult population. It affects nearly 85% of adults [1]. With some patients it occurs only in its acute form. If the problem persists for more than 12 weeks (if pains do not subside after the expected treatment initiated with respect to a specific cause), the disease passes into chronicity and it is referred as a chronic low back pain (CLBP). Etiopathogenesis of CLBP is of a complex character. The prevalence of CLBP is broken down by age groups and by other aspects. The average value of such occurrence, for instance, among the adult population in the U.S., is estimated at approximately 13 % [2]. In recent years the incidence of CLBP increased significantly, in particular by the increasing average age [3, 4]. There are also rising overall costs, which the society must spend in relation with CLBP on health care and subsequent economic costs [5-7]. In the diagnoses of CLBP it has a fundamental role determination of the main underlying cause. From this cause the chosen therapy may be developed. But in many cases we fail to discover the underlying cause, nevertheless the remedial measures need to be done. Part of the CLBP treatment is pharmacotherapy of pain. 

CAUSES OF PAIN, DIAGNOSTICS

Symptoms of LBP can be caused by pathological processes in a number of anatomical structures e.g. intervertebral (facet) joints, intervertebral discs, nerve roots. Etiology is the most often multifactorial in a nature and often there is not a significant correlation between clinical findings, the subjective complaints of patient, findings on imaging methods and the effect of treatment. The pain is mainly nociceptive, but in some cases it may be neuropathic. Some chronic pain syndromes may have both nociceptive and neuropathic components – it is a mixed pain. The outer third of the intervertebral disc and facet joints contain nociceptors. Protracted activation of nociceptors leads to peripheral sensitization and also root compression significantly contributes to neuropathic component of pain [8, 9]. If the pathological stimulus persists, it may lead to peripheral or central sensitization, which plays a key role in chronification of pain. Central sensitization is characterized by increasing excitability of neurons of the central nervous system; the normal stimuli then lead to the abnormal response [10].

A common cause of low back pain is a functional blockade of intervertebral (facet) joints [10]. Nociceptive stimulus may be e.g. entrapment of some of the joint structures [11, 12]. This stimulus evokes not only pain, but also reflex changes in surrounding tissues, such as muscle spasms, myofascial syndrome, trigger points and referred pain, thus a pain in places which are distant from the source of the problem. The reflex changes may also become other nociceptive stimuli and contribute to the maintenance of pain. A number of causes can lead to induction of painful functional blockades of intervertebral joints, such as overloading and improper loading of the spine, muscle imbalance (usually from poor posture), injuries. Painful blockade of the facet joint may be also caused by nociceptive stimulus, whose source can be any structure, innervated by the same spinal segment (e.g. internal organs, muscles) [12].

Another cause of CLBP may be the root pain - compression of nerve roots, which is often caused by the herniation of intervertebral disc. Characteristic for radicular pain is radiation of pain into the lower limb. CLBP may also be caused by spinal canal stenosis in the lumbar region (lumbar spinal stenosis, LSS) with progressive compression of the neurovascular structures. The cause of LSS may be, for example, herniation of intervertebral disc or spondylolisthesis. Most of these are degenerative changes [13]. Degeneration of intervertebral disc is a relatively common cause of CLBP. Its symptoms may not be specific and morphological base is degradation of the matrix in the nucleus pulposus with subsequent further changes in the structure of the intervertebral plate [14]. Psychological factors, particularly stress, anxiety or depression may also contribute to the formation and intensity of pain [15]. To select the appropriate treatment of the source of pain, a good quality diagnostic is needed [16]. Because the creation of the problems may also affect psychosocial factors, it is necessary to perform a thorough personal anamnesis involving lifestyle and diet, work anamnesis, and psychosocial factors. The base of the diagnoses is, in addition to an anamnesis, a thorough clinical examination, while imaging methods, e.g. magnetic resonance imaging (MRI) should be reserved for cases of suspected serious condition. For instance, American College of Radiology recommends not to perform imaging examination unless there are present “red flags” (e.g. a recent serious injury or moderate injury in patients over 50 years of age, unexplained weight loss, or febrile stage, oncological diseases in the anamnesis, focal neurologic deficit with a progressive course) [17- 19]. Generally, at LBP the severity of findings on imaging studies have only insignificant relationship to the degree of subjective symptoms [20]. Because CLBP have often multifactorial causes, for treatment it is necessary multimodal approach with the goal to return patient to active life as early as possible [21]. The main components of treatment besides physiotherapy also includes a pharmacotherapy of pain [22].

PHARMACOTHERAPY OF LOW BACK PAIN

Before starting pharmacotherapy, the elimination of any serious illnesses and other reasons (especially in abdomen, pelvic and thoracic regions) have to be excluded. As the vast majority of back pain belongs to so called simple pain, the priority is to educate the patient about restrictions in physical activity (as short as possible, mostly in range of couple of days) and to inform about the good prognosis (i.e. maintenance of current physical status from a long-term perspective).

Since the pain is always a subjective symptom, its management has to be individually-tailored and closely related to its actually perceived intensity by the patient (as scaled by VAS ‒ Visual Analogue Scale or NRS ‒ Numeric Rating Scale). Apart from non-medicated treatment, several groups of drugs were shown to be beneficial in this pathologic condition ‒ paracetamol, non steroidal anti inflammatory drugs (NSAIDs), opioids, and adjuvant analgesics (e.g. anticonvulsants, antidepressants, muscle relaxants, local anesthetics, collagen, etc.). In general, according to WHO ladder, chronic painful conditions should be treated in order; from drugs with the lowest effects to the stronger ones (step-up approach) and vice versa in acute conditions (step-down approach); so called an "elevator" can be used in case of very intensive chronic pain, where first levels are omitted and strong opioids are given directly. However, current guidelines for low back pain differ substantially and no one strict universal treatment algorithm exists. Different groups of drugs are commonly used as followed. 

Analgesics of first level

LBP is mostly characterized as a nociceptive pain with neuropathic component. Therefore, analgesics present a cornerstone in pharmacotherapy in these painful conditions. Currently, the most commonly used analgesics are paracetamol, as a classical representative of analgesics/antipyretics, and NSAIDs. Paracetamol can be given either alone, in preparations containing this substance together with ingredients facilitating its absorption from gastrointestinal tract (i.e. guaifenesin, caffeine, etc.), or in combinations with weak opioids (codeine, tramadol, hydrocodone). Opioids in monotherapy should be used in the treatment of chronic pain as a second and third step, according to WHO ladder, respectively. 

Paracetamol

Paracetamol (syn. acetaminophen) possesses a still not fully explained mechanism of action, even though several hypotheses have been postulated ‒ inhibition of cyclooxygenase and nitric oxide synthase, modulation of endogenous cannabinoid system, inhibition of serotonergic pathways, etc. [23]. Considering that the majority of currently available tablets usually contain 0.5 g of paracetamol only, many patients are frequently underdosed in common clinical praxis, as the single analgesic dose for adults is 0.625‒1.0 g (i.e. 10‒15 mg/kg) with a maximal daily dose equal to 4 g. Although recommended doses (i.e. 3‒4 g/day) are safe, one has to be careful with patients with concomitant liver disease (i.e. mononucleosis, hepatitis, liver cirrhosis, etc.). Paracetamol, as a classical dose-dependent hepatotoxin, is responsible for almost 50 % of all acute liver failure cases in the U.S., the U.K. and in many Western countries [24]. Additionally, high quality evidence showed that patients with low back pain or osteoarthritis taking paracetamol are nearly four times more likely to have abnormal results on liver function tests, but the clinical importance of this effect is uncertain [25]. 

Non Steroidal Anti Inflammatory Drugs (NSAIDs)

NSAIDs, based on their mechanisms of action, are classified into non-selective (i.e. ibuprofen, diclofenac, naproxen, etc.), selective (syn. preferential) COX-2 inhibitors (nimesulide, etc.), and specific (syn. coxibs) COX-2 inhibitors (celecoxib, etc.). Their therapeutic effects were demonstrated in plenty of clinical trials [26], where they were shown to be superior to placebo. Nevertheless, their benefits in pain with more expressed neuropathic component are very limited [27]. Even though systemically and topically administered NSAIDs are available, systemic administration is assumed to be more beneficial in this indication. No substantial difference in terms of efficacy was recorded between different substances. Importantly, their safety profile (gastrotoxicity ‒ perforation, ulcer bleeding; enterotoxicity ‒ malabsorption, constrictions, etc.; cardiotoxicity ‒ heart failure, stroke, etc.; nephrotoxicity ‒ sodium retention, tubulointerstitial nephritis, etc.; hepatotoxicity ‒ increased level of liver enzymes, decreased liver functions, etc.; bone marrow toxicity, skin toxicity, etc.) is being very commonly the subject of discussion.

Even today, we are still lacking the ideal NSAID in terms of safety, as safety profiles of particular molecules substantially differ each other. Hence, they are not suitable for long-term administration, usually means months/years, i.e. administration is intended for acute treatment. Therefore, some limitations for systemically administered NSAIDs were adopted during last years. For example, a preferential COX-2 inhibitor, nimesulide, was restricted in its indications as a second-line analgesic, while the duration of its administration must not exceed 15 days. Additionally, systemically administered diclofenac should be avoided in patients with congestive heart failure (NYHA II-IV), while the maximal daily dose is 150 mg (diclofenac adjusted in topical formulations is without such a limitation). Even though high doses of ibuprofen (equal to 2.4 g/day) seem to be safe from heart perspective, they should be avoided in patients with serious underlying heart or circulatory conditions or in those who have previously had a heart attack or stroke, as currently recommended by EMA (European Medicines Agency ‒ EMA/217862/2015).

In general, the administration of NSAIDs should be also very carefully weighted in patients concomitantly treated with antihypertensives (blood pressure control worsening [28-30]), selective serotonin re-uptake inhibitors (increased gastrotoxicity [31, 32]), and/or anticoagulants (increased risk of bleeding [33]) even with novel anticoagulants - NOACs (i.e. dabigatran, rivaroxaban, etc.). 

Analgesics of second level

According to WHO ladder, this level is devoted for weak opioids (codeine, dihydrocodeine, hydrocodone, tramadol, etc.). Their primary mechanism of action is the stimulation of opioid receptors being localized both centrally and in the periphery. The only exception is tramadol. It is a racemic molecule having a dual mechanism ‒ stimulation of m opioid receptors (mostly mediated by its active metabolites O-desmethyltramadol) and inhibition of re-uptake ((+)-tramadol inhibits re-uptake of serotonin, (-)-tramadol inhibits re-uptake of norepinephrine) [34].

These are widely used both in monotherapy in various formulations, as well as in fixed combinations with paracetamol as additive/synergic effects are broadly documented [35, 36]. The combinations are usually well tolerated. Hence, they are very suitable for short-term treatment of moderate to severe pain. The dose can be titrated as needed, in case of inadequate control of pain, strong opioids should be prescribed. 

Analgesics of third level

These analgesics involve strong opioids, which should be used in severe pain. Nevertheless, the evidence supporting their reliable effects in this indication remains low [37-39]. All but one representatives bind and stimulate opioid receptors. Only tapentadol, apart from its agonistic activity additionally inhibits norepinephrine re-uptake. Drugs are up-titrated from the lowest dose in order to achieve the minimal therapeutic dose with minimal side-effects (i.e. nausea/vomiting, constipation, itching, sedation, vertigo, etc.). Some adverse effects disappear during the treatment (especially nausea and vomiting), some persist (constipation). Apart from the preference, the minimal dose as possible, and rotating of opioids (based on equianalgesic tables in order to prevent the risk of tolerance), prescription of other drugs alleviating theses symptoms might be necessary. These involve mainly laxatives. More importantly, locally acting opioid receptor antagonists for the treatment of opioid-induced constipation were recently introduced into the common clinical praxis. These can be given either alone (methylnaltrexone i.v., naloxegol p.o.) or in fixed combination with opioids (naloxone + oxycodone). When given orally, they compete with opioids on their receptors in bowel (hence, minimal effect on peristaltic movement) with subsequent extensive first-pass effect (for naloxone around 96 %, hence, minimal systemic bioavailability and analgesic effect of opioid) [40, 41]. 

Other Groups of Drugs

Anticonvulsants

Anticonvulsants might be suitable in predominant neuropathic component, especially in radicular syndromes with pain propagation in lower extremities. Carbamazepine is still very commonly used, however, newer representatives (especially gabapentinoids) started to be used more commonly because of their better safety [27]. Gabapentinoids comprise two clinically used substances ‒ pregabalin and gabapentin ‒ acting as antagonists of alpha-2-delta calcium channel, hence, they prevent the influx of calcium ions into the synaptic button and avoid the release of glutamate into the synaptic cleft. In general, they possess a higher therapeutic index, lower risk of drug-drug interactions and lower incidence of serious adverse effects, however, the evidence of their effectiveness in this particular indication remains low and scarce [42].

Antidepressants

Antidepressants
are suitable especially in patients with comorbid anxiety or depression. Although selective serotonin re-uptake inhibitors (SSRIs) are currently preferred in major depressions, they possess almost null effects in neuropathic pain. Hence, tricyclic antidepressants (TCAs ‒ amitriptyline, nortriptyline, imipramine, etc.) and serotonin-norepinephrine re-uptake inhibitors (SNRIs ‒ venlafaxine, duloxetine, etc.) are preferred [43]; in patients with expressed sleeplessness, trazodone or mirtazapine should be chosen. Moreover, use of antidepressants result in decreased anxiety, sleep improvement, hence, they can improve common daily functioning as well. Nonetheless, even evidence of therapeutic effectiveness of antidepressants remains limited [44]. 

Central muscle relaxants

This therapeutic group involves several drugs (tizanidine, tolperisone, etc.) with distinct mechanism of action. Despite their limited evidence of long-term benefits, they are relatively frequently used in common acute back pain conditions. Nevertheless, their use should be time-limited (as short as possible, i.e. couple of days), as their prolonged administration might result in additional deterioration [45]. Representatives, whose mechanism of action involves modulation of GABAA receptors (i.e. benzodiazepines), possess hypnotic/sedative effects. 

Local treatment

As mentioned above, the evidence of therapeutic effects of local NSAIDs is very low in this indication, hence their administration should not be recommended. On the other hand, positive effects with capsaicin, a selective agonist of the transient receptor potential vanilloid 1 (TRPV1) channel, were retrieved. This interaction is assumed to be responsible for decreased stimulation of peripheral nerves ‒ desensitization [46]. Very similar effects can be, however, achieved by methyl salicylate, which also positively interacts with TRPV1 [47, 48].

Additionally, positive results were obtained with local anesthetics acting as known blockers of voltage gated sodium channels and hence nociceptors at the site of administration. Lidocaine became widely used in postherpetic neuralgia, however, its efficacy in low-back pain was also demonstrated [49]. More recently, substantial reduction in pain intensity after 3 months of treatment in patients experiencing LBP with a neuropathic component was recorded [50]. There is low quality of evidence for beneficial effects of botulinum toxin [51]. 

New choice: injections containing collagen

Local injection application of preparations containing collagen represents an innovative choice of gentle treatment of painful diseases of the musculoskeletal system. Their mechanism of action is different from chondroprotectives, whose effect is directed to the articular cartilage, while collagen injections act complexly. They contain tropocollagen, which induces integrin receptors of fibroblasts and triggers a cascade of growth factors, which are necessary for the formation of new collagen in the connective tissue in the area of ​​application. This mechanism leads the damaged tissue to repair and remodel through new collagen fibers. The result is a reinforcement of the tissue, in which collagen is the basic building unit of e.g. joint capsules, cartilages, ligaments, tendons, bones [52].

One of the causes of musculoskeletal pain is the weakness of internal and external joint stabilization systems, which may arise e.g. on the basis of injuries, poor posture, degenerative changes or rheumatic diseases. As a result of weakened support systems, for example, joint hypermobility, especially in non-physiological directions, arises and leads to the premature wearing of a variety of structures, including further wearing of the support systems and progressive degeneration of cartilage. Hypermobile and weak components of the stabilization systems cause stimulation of local receptors of pain. Therefore, their reinforcement by local application of collagen does not only represent regeneration, but also an antalgic effect. Injectable supplementation of collagen has structural effect, improves the profile of collagen fibers and thereby strengthens the natural support (bio-scaffold) of these systems, strengthens joint capsules, ligaments, tendons, contributes towards strengthening the weak and hypermobile joint systems. It does not only improve the mobility of joints, but it also contributes to release of muscles in the area. Thus, this method  contributes to elimination the causes of pain. The supplementation of collagen can also slow the progression of the disease at degenerative stages, which are associated with physiological down-regulation of metabolism of collagen [52].

Among indications of injections containing collagen belong, for instance, back pain of degenerative origin and arthralgia of large and small joints of the upper and lower limbs. The available medicinal products are differentiated by added ingredient, mostly of phytotherapeutic character, e.g. with anti-inflammatory, regenerating, antioxidant effects.

The concerned injections containing collagen can be applied subcutaneously, intradermally, periarticularly or intraarticularly, i.e. based on type and nature of complaints, both individually and in combination with other drugs. With an advantage they can be applied to the trigger points. Transport of collagen and additional components into the targeted area is based on a patent protected “collagen  delivery system”. At the point, in which the collagen preparation is applied, a temporary collagen matrix is created. From here the ingredients are gradually released into the target area. This process ensures a prolonged effect. Collagen does not interfere with the pharmacokinetics of other drugs, so the advantage of these products is a pain therapy without the risk of drug interactions. Collagen is a body own substance that is supplemented in these preparations in micro supplementary dose and there were no observed allergic reactions even at polyallergic individuals. The advantage of these preparations is the very low risk of adverse effects (e.g. gastrointestinal and cardiovascular), which are characteristic, for example, for NSAIDs, traditionally used in these indications. Combination of collagen injections with analgesics or NSAIDs allows the reduction of these drugs, and thereby the reduction of their adverse effects. For example, the collagen preparation dedicated to LBP, which contains, besides tropocollagen, also extract from Hamamelis virginiana (with anti-inflammatory and anti-oxidant effect) is used at CLBP of various etiology. It is applied periarticularly (subcutaneously) or into the trigger points [52].

Effectiveness of collagen injections in treating CLBP has been confirmed by randomized controlled clinical trial, which enrolled 97 patients with this disease, in the control group trimecaine was used. The results showed that for reaching long and in both groups comparable relief from back pain, in a group with trimecaine, twice as much of rescue medication (paracetamol) was consumed in comparison with the group with collagen MD injections (used combination of three collagen preparations MD – Lumbar, MD Neural and MD Muscle). Collagen injections were well tolerated and they allowed the reduction or discontinuation of the initial analgesic and anti-inflammatory therapy (e.g. NSAIDs, corticosteroids) [53]. 

CONCLUSION 

Chronic low back pain syndrome (CLBP) is one of the most common diseases, which arises from the chronification of acute low back pain. It represents not only a health problem but (due to long term sickness, that causes) also an economic one. As a consequence of the increase in average life expectancy, the incidence of CLBP has been rising. An important part of multimodality treatment of CLBP is a pharmacotherapy of pain. Among systemically used medications belong analgesics (paracetamol, NSAIDs, opioids), anticonvulsants, antidepressants; among topically applied drugs belongs for instance capsaicin. The limiting factor of most drugs currently used in the pharmacotherapy of pain is that there are adverse effects, hence a safer treatment options have been searched for. Injections containing collagen represent a new choice with a good ratio of efficacy and safety. This treatment can be combined with other taken drugs (e.g. NSAIDs). These combinations make it possible to reduce the dose of these drugs, to limit their adverse effects and thus also increase the overall safety of the treatment.
 

CONFLICT OF INTEREST

The author(s) confirm that this article content has no conflicts of interest.

ACKNOWLEDGEMENTS

None declared.

 

REFERENCES

   1.   Balague, F.; Mannion, A.F.; Pellise, F.; Cedraschi, C. Non-specific low back pain. Lancet, 2012, 379(9814), 482-491.

   2.   Shmagel, A.; Foley, R.; Ibrahim, H. Epidemiology of Chronic Low Back Pain in US Adults: Data From the 2009-2010 National Health and Nutrition Examination Survey. Arthritis Care Res (Hoboken.), 2016, 68(11), 1688-1694.

   3.   Juniper, M.; Le, T.K.; Mladsi, D. The epidemiology, economic burden, and pharmacological treatment of chronic low back pain in France, Germany, Italy, Spain and the UK: a literature-based review. Expert Opin Pharmacother., 2009, 10(16), 2581-2592.

   4.   Freburger, J.K.; Holmes, G.M.; Agans, R.P.; Jackman, A.M.; Darter, J.D.; Wallace, A.S.; Castel, L.D.; Kalsbeek, W.D.; Carey, T.S. The rising prevalence of chronic low back pain. Arch.Intern.Med, 2009, 169(3), 251-258.

   5.   Dagenais, S.; Tricco, A.C.; Haldeman, S. Synthesis of recommendations for the assessment and management of low back pain from recent clinical practice guidelines. Spine J, 2010, 10(6), 514-529.

   6.   Delitto, A.; George, S.Z.; Van Dillen, L.R.; Whitman, J.M.; Sowa, G.; Shekelle, P.; Denninger, T.R.; Godges, J.J. Low back pain. J Orthop.Sports Phys.Ther, 2012, 42(4), A1-57.

   7.    Philadelphia Panel evidence-based clinical practice guidelines on selected rehabilitation interventions for low back pain. Phys.Ther, 2001, 81(10), 1641-1674.

   8.   Smart, K.M.; Blake, C.; Staines, A.; Thacker, M.; Doody, C. Mechanisms-based classifications of musculoskeletal pain: part 1 of 3: symptoms and signs of central sensitisation in patients with low back (+/- leg) pain. Man.Ther, 2012, 17(4), 336-344.

   9.   Garland, E.L. Pain processing in the human nervous system: a selective review of nociceptive and biobehavioral pathways. Prim.Care, 2012, 39(3), 561-571.

 (další literatura u autorů)

---

Zdroj: Curr Med Chem 2019;26(6):1019-1026. doi: 10.2174/0929867325666180514102146. PMID: 29756567.