Chronic Low Back Pain: Current Pharmacotherapeutic Therapies and a New Biological Approach
Abstract: Chronic low back pain (CLBP) syndrome represents one of the leading causes of long-term disability worldwide. The prevalence of CLBP has been rising significantly in rela- tion to increasing average life expectancy. CLBP results from chronification of acute low back pain. There are many factors contributing to the CLBP crisis; common etiopathogenetic factors include e.g., functional blockage of intervertebral joints. The treatment of CLBP is complex. An important part of treatment consists of pain pharmacotherapy, for which several groups of drugs are used. The problem lies in the side effects of many of these traditionally used medications. Therefore, new and safer treatment methods are being sought. Innovative options for CLBP pharmacology include injections containing collagen, which can be com- bined with other traditionally used drugs, which helps reduce dosages and increase the overall safety of CLBP therapy.
- 1. INTRODUCTION
Low back pain (LBP) is the most common muscu- loskeletal system disease affecting the adult population. It affects nearly 85% of adults . In some patients it occurs only in its acute form. If the problem persists for more than 12 weeks (i.e., if the pain does not subside after treatment initiated with respect to a specific cause), the disease passes into a chronic stage and is referred to as chronic low back pain (CLBP). Etiopa- thogenesis of CLBP is complex. The prevalence of CLBP is broken down by age groups as well as other features. The average occurrence of CLBP, for in- stance, among the adult population in the U.S., is esti- mated to be approximately 13% . In recent years the incidence of CLBP has increased significantly, particu- larly in relation to the increasing average age [3, 4]. The overall costs, which society must pay for CLBP health care and CLBP-associated economic costs [5-7] are also on the rise. In the diagnoses of CLBP, deter- mination of the main underlying cause is a fundamental step. Afterwards, based on the cause, an appropriated therapy can be developed. However, in many cases, the underlying cause remains elusive, nevertheless reme- dial treatment is still required. Part of CLBP treatment is pharmacotherapy for the associated pain.
*Address correspondence to this author at the Institute of Rheumatology, Prague, Czech Republic; E-mail: firstname.lastname@example.org
- CAUSES OF PAIN, DIAGNOSTICS
Symptoms of LBP can be caused by pathological processes in several anatomical structures e.g., in- tervertebral (facet) joints, intervertebral discs, spinal ligaments, and nerve roots. Etiology is most often mul- tifactorial and often there is no significant correlation between clinical findings, the subjective complaints of patient, findings from imaging methods, and the effect of treatment. LBP pain is mainly nociceptive, but in some cases, it can be neuropathic. Some chronic pain syndromes can have both nociceptive and neuropathic components – i.e., mixed pain. For example: the outer third of the intervertebral disc and facet joints contain nociceptors. Protracted activation of nociceptors leads to central sensitization; peripheral sensitization is mainly due to the presence of inflammation mediators and substances released from immune cells, while any associated root compression introduces a neuropathic component to the pain [8, 9]. If the pathological stimu- lus persists, it may lead to peripheral or central sensiti- zation, which plays a key role in chronification of pain. Central sensitization is characterized by increasing ex- citability of neurons of the central nervous system, i.e., normal stimuli lead to abnormal responses .
As has been said, various pathological processes of anatomical structures can serve as a cause of pain, e.g., pathological processes in intervertebral discs or sprains of spinal ligaments. Since being described as a poten- tial pain generator by Joel Goldthwait in 1911, the facet joint has been increasingly recognized as an important cause of low back pain. It has been estimated that facet joint pathology is a contributory factor in 15–52% of patients with chronic low back pain . The nocicep- tive stimulus may be, for example, associated with en- trapment of related joint structures . This stimulus evokes not only pain, but also reflex changes in sur- rounding tissues, such as muscle spasms, myofascial syndrome, trigger points, and referred pain, which cre- ates pain in places that are distant from the source of the actual problem . Most patients with low back pain have what is often called “non-specific low back pain,” which, in essence, is a diagnosis based on exclu- sion of a specific pathology.
Another cause of CLBP may be nerve root pain as- sociated with nerve root compression, which is often caused by herniation of an intervertebral disc. A char- acteristic for radicular pain is radiation of pain into one or both lower limbs. CLBP may also be caused by spi- nal canal stenosis in the lumbar region (lumbar spinal stenosis, LSS) with progressive compression of neurovascular structures. Possible causes of LSS are herniation of an intervertebral disc or spondylolisthe- sis, which are often degenerative changes . Degen- eration of intervertebral discs are a relatively common cause of CLBP. Its symptoms may not be specific, but the morphological basis is degradation of the matrix in the nucleus pulposus with subsequent changes in the structure of the intervertebral plate .
Psychological factors, particularly stress, anxiety or depression can also contribute to the formation and in- tensity of pain . To select the appropriate treatment, the source of pain needs to be known, making a good diagnosis essential . Additionally, CLBP problems may also affect and be affected by psychosocial factors, therefore, it is necessary to perform a thorough personal anamnesis including lifestyle and diet, a work anamnesis, and psychosocial factors. The basis of a diagnosis, in addition to an anamnesis, also includes a thorough clinical examination, while imaging methods, e.g., magnetic resonance imaging (MRI) should be re- served for cases of a more serious or threatening na- ture. For instance, the American College of Radiology does not recommend an imaging examination unless there are “red flags” present (e.g., a recent serious in- jury or moderate injury in patients over 50 years of age, unexplained weight loss, a febrile stage, oncological diseases in the anamnesis, or a focal neurologic deficit with a progressive course) [17-19]. Generally, with LBP, the severity of findings on imaging studies have an insignificant relationship to the degree of subjective symptoms . Because CLBP often has multiple and complex causes, treatment often requires a multimodal approach with the goal of returning the patient to active life as soon as possible . The main components of treatment, besides physiotherapy, includes pharma- cotherapy for the pain .
- PHARMACOTHERAPY OF LOW BACK PAIN
Before starting pharmacotherapy, other serious ill- nesses and sources of pain (especially in the abdomi- nal, pelvic, and thoracic regions) have to be excluded. Since the vast majority of back pain is simple pain, educating the patient about restrictions in physical activity (mostly for a period of a few to several days) is a priority; next is a realistic prognosis (i.e., the high like- lihood of maintaining current physical status from a long-term perspective).
Since pain is always a subjective symptom, its management has to be individually-tailored and closely re- lated to pain intensity actually perceived by the patient (as scaled using a VAS ‒ Visual Analogue Scale or NRS ‒ Numeric Rating Scale). Apart from nonpharmacological treatment, several groups of drugs have been shown to be beneficial in treating this pathologic condition ‒ paracetamol, nonsteroidal anti- inflammatory drugs (NSAIDs), opioids, and adjuvant analgesics (e.g., anticonvulsants, antidepressants, mus- cle relaxants, local anesthetics, collagen, etc.). In general, according to the WHO “ladder of treatment,” acute conditions should be treated in order using drugs with stronger effects first and moving to the weaker ones (a step-down approach); in chronic pain condi- tions, the reverse strategy is used, and the weaker (best tolerated) drugs are used first, then, as needed, moving to the stronger ones (a step-up approach). The pain "elevator" can be used in cases involving very intense chronic pain, in which the first levels are omitted and strong opioids are given initially. However, current guidelines for low back pain differ substantially and no one strict universal treatment algorithm exists.
The main drugs used for pharmacotherapy of acute pain are NSAIDs, central myorelaxants, and local anesthetics, however, other groups of drugs administered systemically can also be used. In an acute exacerbation of chronic pain, NSAIDs, central myorelaxants (in case of paravertebral muscles spasms) and other drugs (e.g., opioid analgesics) can be used, but only for as long as necessary (due to their adverse effects during long-term administration). Antidepressants or anxiolytics can also be used in patients suffering from chronic pain, if necessary.
In general, any medication used should address the current problems of patients, as well as interindividual variability. For instance, various NSAIDs possess different profiles of adverse effects, which have to be kept in mind with respect to present comorbidities and concomitant medications. Preferential or specific cyclooxygenase-2 inhibitors have been shown to be supe- rior to non-selective NSAIDs in terms of their gastroin- testinal safety, however, the difference is negligible, if any, after several months or years of continuous ad- ministration. NSAIDs seems to be more beneficial in the presence of an inflammatory component, while an tidepressants, opioids, and anticonvulsants usually more beneficial when there is a predominant neuro- pathic component. Both these approaches should be considered in long-term therapy (i.e., for chronic LBP) with respect to their safety risks.
3.1. Analgesics: First Level
LBP is mostly characterized as nociceptive pain with a neuropathic component. Therefore, analgesics are a cornerstone in pharmacotherapy of these painful conditions. Currently, the most commonly used analgesics are paracetamol, which is a classic representative of an analgesic/antipyretic, and NSAIDs (especially locally administered forms). Paracetamol can be given either alone or in preparations containing ingredients facilitating its absorption from the gastrointestinal tract (i.e., guaifenesin, caffeine, etc.). It can also be given in combinations with weak opioids (codeine, tramadol, and hydrocodone). Opioids as a monotherapy should be used in the treatment of chronic pain as a second or third step, according to WHO “ladder.”
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. . Considering that the majority of currently available tablets usually contain 0.5 g of paracetamol, many patients are frequently under- dosed in common clinical praxis, since the single anal- gesic dose for adults is 0.625‒1.0 g (i.e., 10‒15 mg/kg) with a maximal daily dose being 4 g. Although recom- mended 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, is a classic dose-dependent hepatotoxin, and it is responsible for almost 50% of all acute liver failure cases in the U.S., the U.K. and in many Western countries . Additionally, high quality evidence shows that patients with low back pain or osteoarthritis taking paracetamol are nearly four times more likely to have abnormal liver function tests, however, the clinical importance of this effect is uncertain .
3.1.2. 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 have been demonstrated in many clinical trials , where they were shown to be superior to placebo. Nevertheless, their effects on pain with a more expressed neuropathic component are very limited  – their expected effects will be more pronounced in cases with a significant inflammatory component. Even though systemically and topically administered NSAIDs are available, systemic administration is as- sumed to be more beneficial for LBP. Even patients with spinal gout presenting as acute LBP might benefit from NSAIDs and/or the mitotic poison, colchicine.
Although no substantial differences, in terms of efficacy, have been recorded between different NSAIDS, their safety profiles (i.e., gastrotoxicity ‒ perforation, ulcer bleeding; enterotoxicity ‒ malabsorption, con- strictions, etc.; cardiotoxicity ‒ heart failure, stroke, etc.; nephrotoxicity ‒ sodium retention, tubulointersti- tial nephritis, etc.; hepatotoxicity ‒ increased level of liver enzymes, decreased liver functions, etc.; bone marrow toxicity, skin toxicity, etc.) are commonly the subject of discussion.
Even today, we still lack the ideal NSAID in terms of safety, since safety profiles of particular molecules differ substantially from each other. Hence, they are not suitable for long-term administration, i.e., months or years. NSAIDs are intended for acute treatment. Therefore, some limitations for systemically adminis tered NSAIDs have been adopted over the last few years. For example, the preferential COX-2 inhibitor, nimesulide, was restricted in its indications as a second-line analgesic, while the duration of its administra- tion must not exceed 15 days. Additionally, systemically administered diclofenac should be avoided in pa- tients with congestive heart failure (NYHA II-IV), while the maximal daily dose is 150 mg (diclofenac in topical formulations has no such limitation). While high doses of ibuprofen (equal to 2.4 g/day) seem to be safe relative to the heart, they should be avoided in pa- tients with serious underlying heart or circulatory con- ditions or in those who have previously had a heart at- tack or stroke; this is the current recommendation by the EMA (European Medicines Agency ‒ EMA/217862/2015).
In general, the administration of NSAIDs should also be very carefully considered in patients concomi- tantly treated with antihypertensives (worsened blood pressure control [28-30]), selective serotonin re-uptake inhibitors (increased gastrotoxicity [31, 32]), and/or anticoagulants (increased risk of bleeding ) even with novel anticoagulants - NOACs (e.g., dabigatran, rivaroxaban, etc.).
A meta-analysis of 35 randomized placebo-controlled clinical trials (published 2017) with patients suffering from spinal pain demonstrated that NSAIDs are effective in reducing pain, but do not offer clini-ally important benefits above those attributable to pla- cebo. In the short-term follow up, NSAIDs were associated with higher numbers of patients reporting adverse gastrointestinal effects .
3.2. Analgesics: Second Level
According to the WHO “ladder,” this level includes the weak opioids (codeine, dihydrocodeine, hydrocodone, tramadol, etc.). Their primary mechanism of action is the stimulation of opioid receptors localized both centrally and in the periphery. The only exception is tramadol. It is a racemic molecule having a dual mechanism ‒ stimulation of opioid receptors (mostly mediated by its active metabolites O- desmethyltramadol) and re-uptake inhibition ((+)- tramadol inhibits re-uptake of serotonin, (-)-tramadol inhibits re-uptake of norepinephrine) .
These compounds are widely used both in monotherapy and in various formulations, as well as in fixed combinations with paracetamol for the addi- tive/synergic effects, which have been broadly docu- mented [36, 37]. 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 and in cases of inadequate pain control, stronger opioids can be prescribed.
3.3. Analgesics: Third Level
These analgesics include strong opioids, which should be reserved for severe pain. Nevertheless, reli- able evidence supporting their effects on this indication remain scant [38-40]. All but one bind and stimulate opioid receptors. Only tapentadol, apart from its ago- nistic activity, additionally inhibits norepinephrine re- uptake. These drugs should be up-titrated from the lowest dose in order to achieve the minimal therapeutic dose with the fewest side-effects (i.e., nausea/vomiting, constipation, itching, sedation, vertigo, etc.). Some ad- verse effects disappear during the treatment, especially nausea and vomiting, while others, like constipation persist. In addition to the preference for the minimal dose possible, and the rotation of opioids (based on equianalgesic tables in order to prevent the risk of tol- erance), other drugs, which can treat these side effects, might be necessary, which mainly include laxatives. Importantly, locally acting opioid receptor antagonists, for the treatment of opioid-induced constipation, were recently introduced into 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 receptors in the bowels (hence, they minimize the effect on peristaltic move- ment) with subsequent and extensive first-pass effects (for naloxone around 96%, hence, minimal systemic bioavailability and the desired analgesic effect of the opioid) [41, 42].
3.4. Other Groups of Drugs
Anticonvulsants might be suitable when neuropathic pain is the predominant component, especially in radicular syndromes with pain propagation into the lower extremities. Carbamazepine is still very com- monly used, however, newer representatives (espe- cially gabapentinoids) have started to be used more often because of their better safety profiles . Gabapentinoids comprise two clinically used sub- stances ‒ pregabalin and gabapentin ‒ both are of al- pha-2-delta calcium channel antagonists, hence, they prevent the influx of calcium ions into the synaptic but- ton and prevent the release of glutamate into the synap- tic cleft. In general, they possess a higher therapeutic index, lower risk of drug-drug interactions and lower incidence of serious adverse effects, however, evidence of their effectiveness for this particular indication (LBP), remain few and far between .
Antidepressants are suitable especially in patients with comorbid anxiety or depression. Although selective serotonin re-uptake inhibitors (SSRIs) are currently preferred for major depression, they have almost no effect on neuropathic pain. Hence, tricyclic antidepres- sants (TCAs ‒ amitriptyline, nortriptyline, imipramine, etc.) and serotonin-norepinephrine re-uptake inhibitors (SNRIs ‒ venlafaxine, duloxetine, etc.) are preferred ; in patients with expressed sleeplessness, tra- zodone or mirtazapine can be used. Moreover, use of antidepressants result in decreased anxiety and improved sleep, hence, they can improve daily function- ing as well. Nonetheless, evidence for the therapeutic effectiveness of antidepressants remains limited .
3.4.3. Central Muscle Relaxants
This therapeutic group involves several drugs (tizanidine, tolperisone, etc.) that have a distinct mechanism of action. Despite limited evidence for long-term benefits, they are relatively frequently used for acute back pain. Nevertheless, their use should be time-limited (i.e., as short as possible (a couple of days)), since prolonged administration could result in additional deterio- ration . Representatives, whose mechanism of ac- tion involves modulation of GABAA receptors (i.e., benzodiazepines), also possess hypnotic/sedative ef- fects. Considering their harmful effects on axial skele- tal muscles, they should be restricted to short-term use (i.e., a few weeks) only.
3.4.4. Local Treatment
As mentioned above, there is little evidence for the therapeutic effects of local NSAIDs in LBP, hence their administration is not be recommended. On the other hand, capsaicin, a selective agonist of the transient receptor potential vanilloid 1 (TRPV1) channel, has shown positive effects. This interaction is assumed to be responsible for decreased stimulation of periph- eral nerves, i.e., desensitization . Very similar effects can also be achieved with methyl salicylate, which also positively interacts with TRPV1 [48, 49].
Additionally, positive results have been obtained with local anesthetics acting as known blockers of volt- age gated sodium channels in nociceptors located at the site of administration. Lidocaine has become widely used in post-therpetic neuralgia, and its efficacy in low- back pain has also been demonstrated . More re- cently, substantial reductions in pain intensity were recorded in patients experiencing LBP (with a neuro- pathic component) after 3 months of treatment . There is little evidence regarding beneficial effects of botulinum toxin .
Locally administered corticosteroids are commonly given (either epidurally or next to nerve roots), either alone or in combination with local anesthetics. This approach seems to be both empirical as well as evi- dence-based (especially in patients with intervertebral disk displacement ).
A NEW CHOICE: INJECTIONS CONTAINING COLLAGEN
According to the authors of the above mentioned meta-analysis NSAIDs do not offer clinically important benefits above those attributable to placebo and are associated with gastrointestinal adverse effects. The authors state that other meta-analyses demonstrated that paracetamol was also ineffective and opioids only offered small benefits for spinal pain therapy; thus they concluded that there was an urgent need to develop new analgesics for spinal pain . Local injection applications of preparations containing collagen at very low concentrations represents an innovative option for safe treatment of painful diseases of the musculoskele- tal system. Their mechanism of action is different from chondro-protectives, whose effect is directed toward the articular cartilage. Collagen injections act through a more complex mechanism. They contain tropocollagen, which can induce integrin receptors of fibroblasts and triggers a cascade of growth factors, which are neces- sary for the formation of new collagen within the connective tissue located in the area of the application. This mechanism induces the damaged tissue to repair and remodel through the formation of new collagen fibers. The result is tissue reinforcement, in which col- lagen is the basic building unit, in joint capsules, carti- lages, ligaments, tendons, and bones .
One of the causes of musculoskeletal pain is the weakness of internal and external joint stabilization systems, which may arise from injuries, poor posture, degenerative changes or rheumatic diseases. As a result of weakened support systems, joint hypermobility, es- pecially in non-physiological directions, can arise and lead to the premature deterioration of a variety of struc- tures, including further deterioration of the support sys- tems and progressive degeneration of cartilage. Hy- permobile and weaken stabilization system components can also stimulate local pain receptors. Therefore, component reinforcement by local application of colla- gen not only stimulates regeneration, it also has antal- gic effects. Additionally, it not only improves the mo- bility of joints, but it also contributes to the relaxation of muscles in the area. Thus, these products help elimi- nate the causes of pain. Supplementation with collagen can also slow the progression of degenerative diseases, which are associated with physiological down- regulation of collagen metabolism .
Among indications for collagen containing injections are back pain with a degenerative origin and arthralgia of large and small joints of the upper and lower limbs. The available products are differentiated based on added ingredients, mostly with phytotherapeutics, having anti-inflammatory, regenerating, and antioxidant effects.
The injections containing collagen can be applied subcutaneously, intradermally, peri-articularly, or intraarticularly, i.e., based on the type and nature of com- plaints; the collagen can be given alone or in combina- tions with other drugs. An additional advantage is that they can be applied to trigger points.
Below are five specific examples of diagnoses, ap- propriate MD preparations, and recommended methods of application: (1) Lumbago: MD-Lumbar (injected peri-articularly subcutaneously into the proximity of lumbar or lumbosacral joints or into a trigger point), (2) Gonarthrosis: MD-Knee (peri-articularly subcutane- ously or intra-articularly into the knee joint), (3) Cox- arthrosis: MD-Hip (periarticularly subcutaneously or intraarticularly into the hip joint), (4) Shoulder impingement syndrome: MD-Shoulder (periarticularly subcutaneously or intraarticularly into the shoulder joint), (5) Muscle pain: MD-Muscle (intramuscularly into trigger points).
Transport of collagen and additional components into the targeted area is based on a patent protected “collagen injectable drug delivery system.” At the point where the collagen preparation is applied, a temporary collagen matrix is created. From there the other ingre- dients 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 pain therapy without the risk of drug interactions.
Collagen is a naturally occurring substance in the body and these preparations represent a micro supple- mentary dose with no observed allergic reactions, even in poly-allergic individuals. The advantage of these preparations is the very low risk of adverse effects (e.g., gastrointestinal and cardiovascular), which are characteristic of NSAIDs that are traditionally used for these indications. Combinations of collagen injections with analgesics or NSAIDs allows for a reduction in the dose of these other drugs, and thereby a reduction in their adverse effects. .
Effectiveness of collagen injections in treating CLBP was confirmed in a randomized controlled clini- cal trial (2012), which enrolled 97 patients with the disease; trimecaine was used in the control group. The results showed that both groups had comparable relief from back pain, however, the trimecaine group used twice as much of rescue medication (paracetamol) compared to the group with collagen MD injections. Collagen injections were well tolerated, and they facili- tated reduction or discontinuation of the initial analge- sic and anti-inflammatory therapy (i.e., NSAIDs and corticosteroids) .
Chronic low back pain syndrome is a very common disease, which arises from the chronification of acute low back pain. It represents not only a health problem but (due to the associated long term disabilities) also an economic one. As a consequence of increased average life expectancy, the incidence of CLBP is on the rise. An important part of the multimodal treatment of CLBP is pharmacotherapy for the pain. Systemically used medications include analgesics (paracetamol, NSAIDs, opioids), anticonvulsants, antidepressants, while topically applied drugs include, for instance, capsaicin. The limiting factors for most drugs currently used in pain pharmacotherapy are adverse side effects, hence the intensive search for safer treatment options. Injections containing collagen represent a new choice with both good efficacy and safety. This treatment can, as needed, also be combined with other drugs (e.g., NSAIDs). These combinations make it possible to re- duce the dose of the combined drugs, which at higher doses might otherwise have limiting adverse effects, thus combinations can increase the overall safety of pain treatment for CLBP.
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or otherwise.
Funding for this work was provided by grants from PROGRESS-Q35-NEUROL.
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DISCLAIMER: The above article has been published in Epub (ahead of print) on the basis of the materials provided by the author. The Editorial Department reserves the right to make minor modifications for further improvement of the manuscript.
- Pavelka1,*, H. Jarosova1, O. Sleglova1, R. Svobodova1, M. Votavova1, L. Milani2,
- Prochazka3, L. Kotlarova3, P. Kostiuk3, J. Sliva4 and A.M. Meroni5
1Institute of Rheumatology, Prague, Czech Republic; 2University Sapienza, Rome and University of Siena, Italy; 3Edukafarm, Prague, Czech Republic; 4Third Faculty of Medicine, Charles University, Prague, Czech Republic; 5Department of Orthopedics and Traumatology, Niguarda Hospital, Milano, Italy