Advances with analgesics and nsaids for the treatment of spinal disorders

Best Practice & Research Clinical Rheumatology doi:10.1053/berh.2002.0209, available online at http://www.idealibrary.com on7 Advances with analgesics and NSAIDs for the Internal Medicine & Clinical Pharmacology and Toxicology, Division of Clinical Pharmacology and Toxicology and Multidisciplinary Pain Centre, Geneva University Hospital, Geneva, Switzerland Division of Clinical Pharmacology and Toxicology, Multidisciplinary Pain Centre and Division of Internal Medicine of Rehabilitation, Geneva University Hospital, Geneva, Switzerland V. Piguet MDAnesthesiologist & Clinical Pharmacologist and Toxicologist Division of Clinical Pharmacology and Toxicology, and Multidisciplinary Pain Centre, Geneva University Division of Internal Medicine of Rehabilitation and Multidisciplinary Pain Centre, Geneva University Pierre Dayer MDProfessor of Internal Medicine & Clinical Pharmacology & Toxicology Division of Clinical Pharmacology and Toxicology and Multidisciplinary Pain Centre, Geneva University One of the major developments with regard to chronic non-malignant pain in these last few years has been a better understanding of the mechanisms that act to maintain pain, while inferences about the pathophysiology have facilitated therapeutic decision-making.
This chapter reviews the strength of evidence for the therapeutic e€ect of pharmacological symptomatic approaches using non-steroidal anti-in¯ammatory agents, opioids and co- analgesics in acute and chronic back pain with an emphasis on the results of randomized controlled trials as well as on the need for long-term comparative trials of drug ecacy, toxicity Key words: low back pain; analgesics; non-steroidal anti-in¯ammatory agents; NSAIDs; COX-2 selective agents; opioids; anti-depressants; compliance.
*All correspondence to: Dr Jules Desmeules, Geneva University Hospital, Division of Clinical Pharmacology & Toxicology, rue Micheli-du-Crest 24, 1211 Geneva 14, Switzerland. Tel: 0041 (22) 382 99 34; Fax: 0041 (22) 382 99 45; E-mail: Jules.Desmeules@hcuge.ch1521±6942/02/010105‡17 $35.00/00 Non-malignant back pain (BP) encompasses a heterogeneous group of syndromes that are treated in a variety of ways. In contrast to acute pain, chronic BP very often de®es satisfactory treatment. One of the major developments with regard to chronic non- malignant pain in recent years has been a better understanding of the mechanisms that act to maintain pain, while inferences about the pathophysiology have clari®ed Pain syndromes fall into two main categories: the term `nociceptive' is applied to pain that is presumed to be maintained by continuous tissue injury such as bone, joint or muscle in¯ammation. The term `neuropathic' pain is used when pain is believed to be sustained by aberrant somatosensory processing in the peripheral or central nervous system. Although neuropathic pain can respond well to conventional analgesics, these syndromes are disproportionately represented among patients whose pain responds poorly to opioid drugs.As a result, the diagnosis of a neuropathic pain syndrome often implies other therapies, including the use of speci®c non-traditional analgesic drugs such as anti-depr Nociceptive and neuropathic pain can be acute or chronic. The latter is commonly de®ned as pain that persists for longer than the expected time frame for healing or pain associated with a progressive disease of malignant or non-malignant origin.
Chronic or persistent pain may be due to the persistent stimulation of nociceptors in areas of ongoing tissue damage; for example, chronic pain due to osteoarthritis.
Chronic nociceptive or neuropathic pain needs to be distinguished from particular chronic pain syndromes that persist long after the tissue damage that initially triggered their onset has resolved, or pain syndromes without any identi®able ongoing tissue damage or antecedent injury. These syndromes, such as myofascial pain syndrome, ®bromyalgia and somatoform pain disorders, are currently diagnosed on the basis of clinical criteria alone. Knowledge of the underlying pathophysiology of these disorders is limited and pharmacological approaches remain disappointing. The trend over the past decade has been to emphasize the biopsychosocial model and the advantages of a multidisciplinary approach provided by pain centres that carry out comprehensive somatic and psychosocial assessments in addition to providing pharmacological, physical and psychological treatments.BP may refer to various or even mixed components of chronic pain and it is thus not surprising that in most multidisciplinary pain centres back pain is one of the main reasons for consultation.
There is extensive experimental and clinical evidence documenting the major prevalence of persistent pain and the deleterious biological and psychological consequences of under-treated pain. Experimental studies have con®rmed long- standing clinical impressions about the dynamic nature of pain and have shown that inadequately managed acute pain becomes sometimes more dicult to suppress. In fact, if tissue damage is unavoidable, a set of excitability changes in the peripheral and central nervous system take place and sometimes build in a slowly reversible or irreversible pain hypersensitivity in the in¯amed and surrounding Biological and pharmacological evidence has shown that the induction and maintenance of central hyperexcitability and secondary hyperalgesia is mainly mediated by N-methyl-D- aspartate (NMDA) receptor activation, which o€ers a new target for pain modulation in chronic pain patients. Persistent pain syndromes o€er no biological advantage and lead to profound biological alterations in both the peripheral and central nervous systems with a potential `central sensitization' and su€ering.Furthermore, persistent pain profoundly a€ects patients' social relationships, mood and physical functioning.
Advances in pain relief for spinal disorders 107 Concomitant depression and sleep disturbance further decrease overall physical functioning and working disability is typically experienced by chronic pain pa Thus, in order to reduce the neurobiological and psychosocial consequences of pain a prompt, vigorous and adapted management of severe pain is mandatory in acute situations and should run concurrently with the aetiological treatment.
The comprehensive management of quality of life in rheumatology encompasses the control of in¯ammation, the prevention of joint destruction, the maintenance of optimal function and the management of pain. Non-pharmacological interventions, including patient education, psychological support and physical and occupational therapy play a crucial role in the management of chronic pain.
Chronic pain often remains an intricate syndrome where analgesic prescription is only one part of the treatment. However, when analgesics are tailored by taking into account their pharmacological properties and the patient's pain syndrome and co- morbidities, they may contribute to a favourable bene®t/risk ratio.
PHARMACOLOGICAL APPROACHES TO NOCICEPTIVE PAIN Various chemicals (bradykinin, histamine, serotonin, prostaglandins, potassium, protons), which are released after tissue damage, induce nociceptive reactions and modify the activity of nociceptors either by direct activation or by modula Several peptides are present within the primary a€erent ®bres and their pro®le can be altered by sustained stimulation or by damage to the nerve. Apart from these substances, which are liberated soon after tissue damage, other factors such as the cytokines (interleukins, interferon, tumour necrosis factor (TNF) and nerve growth factor), are released by phagocyte cells and cells of the immune system and have an To treat acute or persistent nociceptive pain in rheumatological conditions, pharmacological approaches, which encompass anti-in¯ammatory and immunomodu- latory agents such as glucocorticoids, methotrexate, ciclosporin, anti-TNF, le¯uno- mide, mycophenolate mofetil, disease modifying antirheumatic drugs (DMARDs), are targeted to the originating factors.
However, many patients remain insuciently relieved and symptomatic analgesic therapy is needed. The World Health Organisation (WHO) recommends a three-step ladder approach to the use of analgesic drugs, with an initial treatment choice of a non- opioid analgesic, either non-steroidal anti-in¯ammatory drugs (NSAIDs) or acetamino- phen. If one of these agents fails to relieve pain, a `weak' opioid for mild to moderate pain is used, either alone or in combination with a non-opioid analgesic. If pain persists or increases, a `strong' opioid for moderate to severe pain should be substituted. Current non-opioid and opioid analgesics have their limitations and physicians' and patients' fears ofadversee€ects associatedwithopioidsand NSAIDscontributeto theunder-treatment of pain. The `analgesic ladder' approach of the WHO is widely accepted as the basis for treatment guidelines of cancer-related nociceptive syndromesand this approach is nowadays extended to non-cancer pain, although scienti®c evidence is still missing.
BENEFITS AND LIMITS OF NSAIDS AND ACETAMINOPHEN Finding the best clinically available evidence for making decisions about the selection of an analgesic in painful spinal disorders remains a necessary purpose. Systematic reviews of randomized controlled trials provide the best level of evidence for selecting a treatment, despite some pitfalls such as the inclusion of low-quality trials, unpublished trials and the many variations possible among drugs, doses, routes of administration and pain conditions which make meaningful comparisons dicult.
Single-dose analgesic trials using reproducible clinical procedures (dental extraction, post-surgical, or post-partum models) are not sucient to assess their value in clinical practice, although such trials may be helpful in determining the relative ecacy of NSAIDs. E€ective relief can be achieved in these models with oral non-opioids and NSAIDs. The results of a meta-analysis that included 42 randomized, controlled trials using these models allowed the comparison of the dose±response curves for diclofenac and ibuprofen, for example. Although diclofenac has long been regarded by clinicians as a more e€ective NSAID than ibuprofen, they both showed the same level of ecacy when the dosage was adjusted, i.e. 50 mg of diclofenac orally was no more ecient than 600 mg of ibuprofenWith regard to BP, a systematic review that included 51 randomized, controlled trials (6057 patients) that assessed the bene®ts of NSAIDs, suggested that there was a signi®cant clinical bene®t over placebo and a strong level of evidence that various types of NSAIDs were, somehow, equally e€ective for the short- term relief of acute BPFor chronic in¯ammatory BP one study has suggested that a 1-year trial might be of optimum value compared to a 6-week assessment in order to de®ne better the ecacy and tolerability of NSAIDs in ankylosing spondylitis.
Evidence of long-term ecacy from randomized, controlled trials is still lacking and safety issues remain the most important pr The most commonly prescribed NSAIDs reduce the synthesis of prostaglandins and thromboxane by the inhibition of the enzyme cyclo-oxygenase 1 (COX-1), a constitutive form of the enzyme. Inhibition of COX-1 is responsible for the gastrointestinal irritation and ulceration and for the blockade of platelet aggregation.
The COX-2 inducible form of the enzyme is selectively inhibited by various new COX-2 NSAIDs that reduce the risk of these adverse e€ects and are e€ective in relieving the chronic pain conditions associated with rheumatoid arthritis or osteoarthritisThe rate of con®rmed gastrointestinal events in 8076 randomized rheumatoid arthritis patients who received 50 mg of rofecoxib daily was 50% lower than the rate observed with naproxen 500 mg twice daily (4.1 events/100 patient-years). A number of studies in patients with osteoarthritis, rheumatoid arthritis and acute pain have con®rmed that the clinical ecacy of COX-2 selective inhibitors is similar to that of conventional NSAIDs.Rofecoxib is currently licensed in Europe only for the treatment of osteoarthritis. Some other selective COX-2 NSAIDs such as nimesulide have been investigated in BP. A randomized prospective double-blind trial evaluated the ecacy of nimesulide (100 mg twice daily for 10 days) claimed to be COX-2 selective agent versus ibuprofen (600 mg three times daily) in 104 patients (18±65 years) su€ering from acute common BP. There was a clear improvement in all parameters of pain and back function from the third day of treatment onwards with both treatments versus placeboA 6- week randomized controlled study in 246 patients with ankylosing spondylitis showed an improvement in pain and functional impairment that was greater in the celecoxib or ketoprofen 200 mg/day treatment groups than in the placebo grSince the available COX-2 selective inhibitors are still not `pure' COX-2 drugs, especially if considering nimesulide, they may not display as dramatic an improvement on the adverse e€ects pro®le as was previously hoped. Well-documented cases of acute hepatic injury have been reported with nimesulide and with a number of NSAIDs such as diclofenacFurthermore, COX-2 selective agents are not expected to di€er in terms of cardiovascular and renal adverse events, particularly when one takes into account the Advances in pain relief for spinal disorders 109 long half-life of rofecoxib or celecoxib compared to the classically short-acting non- This can be of particular concern for the elderly population, who commonly experience chronic pain with acute exacerbations. Indeed, the available data demonstrate that the same frequency and type of renal toxicity should be expected with the new selective COX-2 inhibitors as with the NSAIDs. The selective COX-2 inhibitors represent a real therapeutic advance with a better gastrointestinal safety pro®le, but their renal safety has yet to be demonstrated, especially when used in high- risk patients or with other drugs that in¯uence the renal haemodynamics. This assertion is borne out by recent clinical studies showing that the COX-2 inhibitors rofecoxib and celecoxib produce qualitative changes in urinary prostaglandin excretion, glomerular ®ltration rate and sodium retentIt is, therefore, unlikely that these COX-2 selective inhibitors will have greater renal safety bene®ts over non-selective NSAID therapies, and it is reasonable to assume that al NSAIDs, including COX-2-selective inhibitors, share a similar risk for adverse renal e€ecThese adverse e€ects include functionally acute renal failure, sodium and water retention, hyperkalaemia and immunoallergic nephritis. Moreover, it is possible that the improved gastrointestinal safety will increase the use of the selective COX-2 inhibitors in older and high-risk patients, which may lead to more renal adverse e€ects. The overall incidence of adverse renal events after celecoxib was similar to that observed after NSAID use in a post-hoc analysis of the renal toxicity of celecoxib, using the safety database generated during its clinical development programme which included data from more than 5000 subjects.
The burden of il ness resulting from NSAID use may exceed that resulting from renal damage in the elderly. A recent case±control study showed that the use of NSAIDs, other than low-dose aspirin, in the previous week was associated with a doubling of the odds of a hospital ®rst admission with cardiac heart failure (adjusted odds ratio (OR) ˆ 2.1) with a greater increase when patients had a history of heart disease (OR ˆ 10.5) compared to those (OR ˆ 1.6) without such a history. The odds of a ®rst admission to hospital with cardiac heart failure was positively related to the NSAID intake dose in the previous week and was increased to a greater extent because of the long half-life of NSAIDs. Assuming these relationships are causal, it was estimated that NSAIDs were responsible for approximately 19% of hospital admissions for cardiac heart failurTherefore, the long half-life of NSAIDs in particular should be used with caution in patients with a history of cardiovascular disease.
Furthermore, the rate of serious thrombotic adverse events (such as myocardial infarction) was signi®cantly higher in patients receiving rofThe most likely explanation for the di€erence in cardiovascular events is that there is a protective e€ect of naproxen use, possibly related to anti-platelet activity. That is, a large number of elderly patients should remain on aspirin if they receive celecoxib or rofecoxib. In this case, the advantage in terms of gastrointestinal tract security remains an open question.
In 2000, 1120 safety issues were reported to the Committee on Safety of Medicine in the UK for rofecoxib on 557 000 estimated prescriptions. Half of these issues concerned the gastrointestinal tract (GI), while 12% concerned bleeding, ulcers and perforations. Five patients had a fatal outcome. Over two-thirds of the patients were over 65 years in age and a quarter were taking The Committee on Safety in Medicine in the UK also reminded practitioners that COX-2 selective inhibitors were contraindicated in the presence of an active peptic ulceration or GI bleeding. Celecoxib, in the CLASS study, at dosages greater than those indicated clinically, was associated with a lower incidence of symptomatic ulcers and ulcer complications, compared with NSAIDs at standard dosages; however, this bene®t was reduced in patients taking aspirin concomitantly.
Indeed, in terms of safety and cost, short half-life NSAIDs, even if they are not COX-2 selective agents, can still be considered in acute painful conditions. This is especially the case when chronic persistent nociceptive pain is a€ected by short-lasting acute exacerbation. When moderate pain persists, either COX-2 selective agents such as celecoxib or rofecoxib or the combination of classical NSAIDs with a proton pomp inhibitor when digestive risk factors have been identi®ed, can be used.
Several non-NSAIDs non-narcotic therapies are available when in¯ammation is not the foremost issue in pain management. Since its introduction in 1893, acetaminophen has been widely used for the treatment of pain. Despite many attempts to elucidate its mechanism of action, it still remains unclear. It has been shown that acetaminophen selectively inhibits central nervous tissue COX but has little e€ect on enzyme preparations from peripheral Although this is not unequivocally accepted, many experiments in animaand humanhave suggested that descending spinal serotoninergic pathways are essential for maintaining its ecacyThis centrally acting analgesic is devoid of the gastric or renal adverse event pro®le usually seen with NSAIDs. Acetaminophen is as e€ective as NSAIDs for the management of mild-to- moderate osteoarthritic pain. The advantages is of NSAIDs over acetaminophen in painful spinal conditions remain at best, con¯icting, and acetaminophen is still the ®rst- line therapy recommended by the European and American societies of Rheumatol- for treating pain associated with osteoarthritis and is safer in the elderly Primary care physicians frequently face the challenge of treating chronic debilitating pain. Whether or not treatment with opioids is e€ective and justi®ed in the treatment of pain that is unrelated to cancer is a matter of great controversy. In recent years, growing experience with opioid administration in cancer patients and the publication of some controlled studies have promoted a more liberal attitude. Certain carefully selected patients could bene®t from short-term opioid treatment within the context of a more permanent pain treatment regimen. However, potential pitfalls such as prescribing opioids for myofascial pain syndrome, ®bromyalgia, or somatoform pain disorders should be taken into account as well as the psychosocial dimensions surrounding the prescription of opioids.
In chronic nociceptive pain conditions, regular use of low-dose, long-acting opioids, although controversial, can e€ectively control chronic pain in selected pati Opioids can improve the quality of life of patients in pain, but their use requires particular precautions, both in the choice of the speci®c opioid and in singling out patients with a high risk of drug abuse. Several randomized controlled studies have been performed in rheumatological chronic pain conditions evaluating the ecacy of opioids in BP. An open, randomized 4-month comparison of naproxen and two opioid regimens of oxycodone and sustained-release morphine sulphate in 36 patients with chronic BP has been performed. The opioid groups were signi®cantly better than the naproxen alone group, with less pain and emotional distress, but opioids had little impact on daily activity and sleep and one of the participants showed signs of aAnother study evaluated 380 chronic BP outpatients (aged 21±79 years) enrolled on an enriched 1-month randomized placebo controlled tDuring the preceding 4-week open- label phase, patients were treated with tramadol in doses up to 400 mg/day. Because of adverse events, 20% withdrew, but 254 patients entered the double-blind phase, during Advances in pain relief for spinal disorders 111 which daily doses were maintained (200±400 mg tramadol) and compared to placebo.
The Kaplan±Meier estimate of the cumulative discontinuation rate due to therapeutic failure was 20% in the opioid group compared to 51% in the placebo grIn osteoarthritis, a randomized controlled study on 236 patients (mean age 60 years) showed that the addition of an opioid al owed for a reduction in NSAIDs without compromising pain relieThis can be of bene®t in the mainstay of chronic pain management, since NSAIDs are known to be associated with cardiac and renal toxicities, a particular problem for the elderly population.
Although some open-label studies have suggested a possible bene®t of long-term opioid analgesic therapy for some well-selected patients with refractory BPfactors responsible for chroni®cation, such as the psychosocial situation, should systematically be taken into account and an interdisciplinary approach to the treatment of pain should be proposed. This is the case for common BP, ®bromyalgiaor failed back surgery where nociceptive and neuropathic pain syndromes may, moreover, coexist; one should therefore be extremely cautious as far as opioid prescription is concerned.
Choosing the optimal analgesic treatment is not easy considering the multitude of currently available opioid derivatives, the commercialization of new galenic preparations, and the diculty of evaluating their risk/bene®t ratio. Basic principles for selecting an opioid treatment on an individual basis rely on various selection criteria such as the pharmacodynamic (PD) and pharmacokinetic (PK) properties of available opioids, the presence of comorbidities and concomitant medications, and the PK situations that are prone to increase the risk of substance abuse.
Addiction is a concern among patients and health-care providers, and drug-seeking behaviour is seen among patients with chronic pain. When opioids are used appropriately, addiction is rare, but patients should be monitored to ensure that they are using the opioid correctly. The risk can be minimized by prescribing opioids to patients with a history of drug abuse only with great caution and under strict medical supervision. To reduce the risk even further, the drug chosen should be given at the lowest e€ective dosage, with regular monitoring, have the least addictive potential and not be prescribed inde®nitely. The risk of addiction can be reduced by avoiding their prescription in pain syndromes that are poorly responsive to opioids, such as psychogenic or neuropathic pain, and by selecting an opioid with an appropriate PK and PD pro®le. Certain PK drug characteristics lower the addiction potential. The rate of CNS drug delivery for example, in¯uences positive reinforcement. Giving an oral formulation, a slow release formulation, or even a drug whose opiate component necessitates bioactivation, such as codeine or tramadol, reduces the risk of addiction. An optimal PK pro®le would also avoid negative reinforcement such as physical dependence and this can be accomplished with slow release formulations or long half-life opioids.
Physical dependence should be sharply di€erentiated from addiction. Physical dependence can occur in the clinical setting, but does not involve inappropriate drug-seeking behaviour. Withdrawal symptoms and signs can be prevented by gradually decreasing the opioids' dosages. An optimal PD pro®le would favour selectivity on m opioid receptors and avoid a high intrinsic activity.
Pain is often inadequately treated due, in part, to a reluctance to use opioid analgesics and fear of abuse behaviour. Every day throughout the world patients, caregivers and their governments face diculties in obtaining opioid analgesics for the relief of severe pain. The WHO has promoted guidelines to avoid national narcotic laws that interfere with making these drugs available for medical use. These guidelines, recognizing that physicians should have the ¯exibility to decide the dose and duration of opioid treatment based on individual patients' needs, recommend that a country's narcotic legislation not restrict the amount of opioids prescribed at one time and a survey conducted by the International Narcotics Control Board shows that 52% of governments do not have this provision in their legislat A retrospective survey of medical records from 1990±1996 stored in the databases of the Drug Abuse Warning Network and the Automation of Reports and Consolidated Orders System in the USA from 1990±1996 showed an increased medical use of opioid analgesics to treat pain, but that did not seem to contribute to an increase in opioid abuse.Among opioids, tramadol is not scheduled in the USA and Europe and it has been recently marketed in the USA. A proactive post-marketing surveillance programme was carried out; monthly population exposure to tramadol had grown to just under one million patients over a 3 year period. Reports of abuse over the same period, however, grew no higher than 2/100 000 patients, recorded during a brief period of experimentation in the ®rst 18 months. Since then the reported rate of abuse has signi®cantly declined to levels of less than 1/100 000 patients by the year 2000.
Moreover, 97% of abuse cases occurred in patients with a history of drug abuse. Because of its dual mode of action, tramadol, compared to other opioids, may have a better safety pro®le. On the down side however, the monoaminergic pro®le may increase CNS susceptibility. Convulsions, for instance, have been described with tramadol, although this occurred mainly after overdoses. In addition, due to the monoaminergic action of tramadol, concomitant anti-depressants should be used with caution to avoid a In case of insucient control of pain symptoms, the use of a `stronger' opioid such as a slow release morphine formulation can be recommended when one bears in mind the prescribing guidelines for non-cancer pain IS THERE A ROLE FOR ANTI-DEPRESSANTS IN THE MANAGEMENT There is evidence that anti-depressants (ADs) have pain relief e€ects, which are either acute as observed in experimental pain studies or chronic as demonstrated in patientsTherefore, they have been commonly used to treat chronic pain for years. There are many assumptions about the mechanisms involved in the analgesic e€ects of ADs. Tricyclic ADs are known to inhibit noradrenaline (NA) and serotonin (5-HT) pre-synaptic re-uptake, but they also block a1 adrenergic, muscarinic and H1 histaminergic receptors. Some of the tricyclics present a balanced inhibition of NA and 5-HT re-uptake, such as amitriptyline or imipramine, or a relatively selective inhibition of NA re-uptake, such as desipramine or the tetracyclic maprotiline. The selective serotoninergic re-uptake inhibitors (SSRIs) act mainly on 5-HT. A new agent, venlafaxine, which is chemically distinct from tricyclics and SSRIs, has shown an inhibition in re-uptake of NA and 5-HT with a relatively selective action on 5-HT, Some authors have argued that ADs might decrease pain through the improvement of masked or manifest depression. Although an improvement in mood may contribute to reports of decreased pain in some patients, there is clear evidence for pain relief in patients without pre-existing mood disorders and with smaller doses than the usual doses recommended for depreThe relationship between depression and pain could be even more complex, since an antagonist for substance P, which is a peptide involved in pain endings in the spinal cord, has shown anti-depressant properties that are equivalent to parAs well as their inhibitory mechanisms on 5-HT and/or Advances in pain relief for spinal disorders 113 NA re-uptake, their analgesic e€ects could also be mediated through an involvement in the opioidergic system. ADs have additional e€ects on various ion channels such as inhibition of cardiac or neuronal Na‡ channels. This latter blockade could be involved in the analgesic e€ects of ADs. Some authors have claimed that the analgesic e€ect of ADs could be an epiphenomenon of their sedative e€ects. Meta-analysis has shown that non-sedative ADs are as e€ective as sedative ones. Furthermore, lorazepam, a benzodiazepine, did not relieve neuropathic pain, in contrast to aThe majority of clinical trials that have assessed the analgesic e€ects of ADs have done so using subjective scales usually rating pain intensity, fatigue, sleep, physical or social activities and quality of life. Numerous clinical trials have been done with ADs in various chronic pain syndromes. Evidence of their ecacy is conclusive for diabetic neuropathy, post-herpetic neuralgia, atypical facial pain, tension and migraine headache, ®bromyalgia, rheumatic pain and chronic pain of mixed aetiol Evidence is less clear for chronic BP given the methodological biases in many of the studies e.g. small sample sizes that lack statistical power, inadequate speci®cation of inclusion and exclusion criteria, failure to use standardized outcome measures, absence of rigorous assessment for major depressive disorder and failure to maintain study Furthermore, the di€erences among the chronic back pain studies in terms of patients' characteristics, medications, doses and outcome measures limit the use of a meta-analysis for a synthesis of this literature. In two recent placebo-controlled studies, which included patients su€ering from chronic BP referred to primary practice, nortriptyline and maprotiline showed an analgesic e€ect in non-depressed individuals and were also associated with a lessening of disability in daily functioning, predominantly in the psychosocial domain.These gains seemed to be more important for patients with radicular pain. Further studies are needed to investigate the e€ect of ADs on chronic BP with a neuropathic pain component. As in the experimental assays, the numerous clinical studies used the whole range of ADs from the ®rst tricyclics to the newest ADs such as SSRIs causing fewer severe adverse e€ects. A large majority of these studies used a tricyclic, particularly amitriptyline, which was superior to placebo or to a SSRI. More speci®cally, in neuropathic pain, most of the studies showed a higher ecacy of tricyclics compared to These conclusions were con®rmed in meta-analyses and non-selective tricyclics remain the most e€ective. Several dose±response studies in patients did not produce consistent ®ndings regarding the relationship between dose, serum levels and analgesic e€ect.
There is no established therapeutic concentration of ADs and as a consequence no dosing recommendations for AD use in any chronic pain disorder, re¯ecting the importance of ®rst considering individual metabolic capacity. Thus, the monitoring of plasma drug concentrations should be restrained to compliance or toxicity problems or ineciency after an adequate period of treatment. ADs are associated with a relatively high incidence of adverse e€ects in therapeutic usage. Many of the commonly observed adverse e€ects, such as dryness of mouth, blurred vision and drowsiness can be troublesome particularly at the start of tricyclic treatment. Studies have shown higher adverse e€ect scores at the start of treatment than 4±6 weeks later. The most common cardiovascular adverse e€ect appears to be orthostatic hypotension; more severe cardiac complications could arise in subjects with pre-existing cardiovascular disease. There appears to be a dose-dependent relationship such as has been found for venlafaxine and frequency of hypertension. In a meta-analysis, the risk of central toxicity (e.g. tremor, ataxia) was positively correlated with plasma drug concentration.
Advances in pain relief for spinal disorders 115 Compliance has been de®ned as `the extent to which a person's behavior (in terms of taking medication or executing lifestyle changes) coincides with medical or health adviceNon-compliance may refer to many behaviours such as not having a prescription ®lled, taking an incorrect dose, taking the medication at the wrong times, forgetting one or more doses of the medication, increasing the frequency of doses and stopping the treatment too soon, either by ceasing to take the medication sooner than the physician recommended or failing to obtain a re®ll prescription. The most common forms of non-compliance are delaying or omitting doses except for narcotic analgesics Although consistently found to occur in about one half of all patients, non- compliance has been found to vary according to the type and state of disease.
Chronicity is associated with decreased compliance as shown in some chronic pain problems such as headac, rheumatoid arthritisand ankylosing spondylitis During the last decade many methods have been devised to assess compliance, but the complexity of the problem has prevented the development of a `gold standard' method of measurement. The most frequently used methods are drug levels in blood or urine as direct measures and interviews, diaries and tablet counts (e.g. medication event monitoring system (MEMS)) as indirect measures.
For patients, compliance is not an issue: they do not perceive taking drugs entirely in terms of obeying the doctor's orders. Instead, they weigh up the costs and bene®ts of taking a particular medication, as they perceive them within the contexts and the constraints of their everyday lives and needs. This perspective implies the patient's active participation in the therapeutic relationship, leading to a shared decision making process. It also implies that non-compliance may not be due to disregard for the doctor's orders but may result from reasoned behaviour based on the patients' beliefs and previous experiences. Compliance appears to be high when practitioners and patients have common representations, agree on treatment procedures and share criteria for Studies have shown that adverse e€ects and beliefs about adverse e€ects are major determinants of non-compliance in patient populations su€ering from a variety of diseases or problems. Occurrence and severity of adverse e€ects have been described as decreasing compliance to cholesterol-altering drugs, to anti-epileptic drug regimes as well as to migraine medication.Non-compliance due to fear of becoming dependent on the medication has been pointed out in populations as divergent as asthmatic patients, general practice patients taking long-term medication or patients su€ering from ankylosing Such ®ndings in rheumatoid arthritis and ankylosing spondylitis patients may lead them to consider compliance with medication intake as a last resort, when the symptoms are more unacceptable than the fears of adverse e€ects For ADs, a fear of adverse e€ects has been shown in depressive patients as well as in the general populaThe results of a large opinion poll in Germany showed that even for the treatment of severe mental disease, psychotropic drugs are not well accepted in comparison to cardiac drugs: they are believed to cause signi®cantly more severe adverse e€ects and raise a greater fear of losing contrHowever, a patient's attention to adverse e€ects does not only lead to compliance problems. Wynne & Lonstudy has shown that this attention might help the patient to cope adequately with his/her medication intake and thus avoid detrimental adverse e€ects. Adverse e€ects are thus of major interest when dealing with medication intake Since information about chronic pain patients' beliefs on ADs is scarce, we have conducted a pilot study to investigate these beSeventy-six chronic pain patients (CPPs) and 54 pain-free non-patient controls (Cs) were included. CPPs were repre- sentative of the population referred to the Geneva Multidisciplinary Pain Centre and the sample included 30 chronic back pain patients (CBPs) and 46 patients su€ering from other chronic pain problems; Cs were matched for age, gender, socioeconomic status and nationality. Semi-structured interviews were conducted, explicitly referring to individuals' de®nitions of medication and ADs. We chose to ask the individuals to give their own de®nitions instead of using multiple-choice questionnaires, since the latter mainly call up recognition memory. Moreover, the items in a questionnaire might inhibit a further search for alternative answers. The data analysis procedure was a content analysis. All responses were transcribed and categorized. Bivariate statistical procedures were used to evaluate within-group and between-group di€erences.
Apart from depression, CBPs' description of the indications for ADs included mood improvement, soothing e€ects, but also loss of desire. Pain was more often mentioned in this group However, this response was much less frequent than expected when compared to their reported intake of ADs and also to their medical records.
One-third of the CBPs considered that ADs were used to address severe psychological problems including madness, and 19% of them expected ADs to induce personality changes. Accordingly, 24% of CBPs considered ADs to be a dangerous medication, having many adverse e€ects including addiction (37%). Up to 19% would refuse to take ADs, 41% would accept but with great reluctance and 33% would accept only if they were convinced that it would a€ect their pain problem. The e€ect of ADs on pain is barely known among chronic pain patients. Patients' beliefs may hinder their understanding of the physician's prescription and their compliance with it. Non- congruence between patients' beliefs and physicians' prescription may account for part of the diculties when prescribing such medication.
We have also been investigating the way individuals get information about medicaPatient information lea¯ets (PILs) were the main reported source of information about medication in the patients as well as in the controls. Expected `ideal' information included the possibility of discussing PILs and adverse e€ects with the physician. Content analysis of the PILs showed that lea¯ets on ADs point to indications that have a clear psychological, if not psychiatric, connotation. This is in line with patients' and controls' representations of ADs, so they may consider such medication to be inappropriate for the treatment of pain. In the context of chronic pain, where the Table 2. Intake of ADs and beliefs about AD medication.
Advances in pain relief for spinal disorders 117 causes of pain persistence often remain elusive, prescription of ADs may be seen as a `delegitimation' ± referring to the denial of the patient's experience of pain and su€ering.Even when ADs are prescribed because of their analgesic e€ect, indications as described in the PILs may lead the patient to think that the physician does not truly believe s/he is in pain. Thus, non-congruence between the motive for prescribing ADs and PILs may also account for part of the diculties when prescribing such medication.
A study conducted with a sample of the Geneva population aged 18±75 showed that the vast majority of the interviewees did not di€erentiate between the various classes of psychotropic drugs (PTDs) and their use for psychiatric illnesses.Similarly, for PTDs, more than 80% of the subjects referred to real or presumed somatic and/or psychological harmful e€ects (e.g. lethargy or drowsiness, loss of contact with reality, changes of personality). They criticized, in the same proportion, the addiction and the dependency created by PTDs and society itself, which promoted their use. Subjects' attitudes regarding PTDs, as well as medication in general, and compliance were strongly associated. Thus, both aspects seemed to be related to the subjects' degree of adherence to medicine and to its therapeutic approaches.
Experimental studies have con®rmed long-standing clinical impressions about the dynamic nature of pain and have shown that inadequately managed acute pain may become more dicult to suppress. Persistent pain syndromes o€er no biological advantage; they could be the result of profound neurobiological alterations and be complicated by major psychosocial consequences. In order to reduce the neurobiolo- gical peripheral or central sensitization and the psychosocial consequences of severe pain, one should uncompromisingly handle acute pain in parallel to the ñtiological Chronic pain syndromes fall into several main categories that imply di€erent therapeutic strategies. As a result, nociceptive pain can be adequately reduced using NSAIDs, acetaminophen or opioids, whereas neuropathic pain often implies the need for other therapeutic approaches including the use of speci®c non-traditional analgesic drugs such as anti-depressants or anti-convulsivants.
For nociceptive pain the selective COX-2 inhibitors are a real therapeutic advance with a better gastrointestinal safety pro®le, but their renal and cardiovascular safety are not expected to be particularly di€erent when one takes into account the long Indeed, in terms of ecacy, safety and cost, short half-life NSAIDs, even if they are not COX-2 selective agents, can still be suggested for use in acute painful conditions. This is especially the case when chronic persistent nociceptive pain is a€ected by short-lasting acute exacerbations. When moderate pain persists, either COX-2-selective agents such as celecoxib or rofecoxib or a combination of the classical NSAIDs with a proton pump inhibitor when digestive risk factors are identi®ed, can be used. Several non-NSAID non-narcotic therapies such as acetaminophen are available when in¯ammation is not the foremost issue in pain management and they remain the ®rst choice analgesic for mild to moderate nociceptive non-malignant pain. In chronic nociceptive pain conditions, regular use of low-dose long-acting opioids, although controversial, can e€ectively control chronic pain in selected patients. Opioids can improve the quality of life of patients in pain, but their use requires particular precautions, both when choosing the opioid and when singling out patients at risk of drug abuse. There is evidence that anti-depressants o€er bene®ts in chronic pain: meta-analyses have con®rmed that non- selective tricyclics remain the most e€ective especially when a neuropathic component is present. Like any pharmacological treatment, anti-depressants raise the issue of patients' compliance. Various factors, such as beliefs and previous experiences, may a€ect it. The analgesic e€ect of anti-depressants is barely known, whereas the adverse e€ects are highly emphasized. Regarding beliefs, the case of opioids has not yet been settled by both patients and therapists.
Chronic pain remains an intricate syndrome where analgesic treatment is only one part of the treatment. However, when analgesics are tailored to the individual by taking into account their pharmacological properties and the patient's co-morbidities, they may contribute to a favourable bene®t/risk ratio in these complex clinical conditions.
. distinguishing nociceptive from neuropathic and somatoform pain disorders (or components) will help in selecting the best therapeutic approach . in terms of ecacy, safety and cost, short half-life NSAIDs, even if they are not COX-2 selective agents, can still be suggested for use in acute painful conditions.
This is especially the case when chronic persistent nociceptive pain is a€ected by . the selective COX-2 inhibitors are a real therapeutic advance with a better gastrointestinal safety pro®le, but their renal and cardiovascular safety has yet to be demonstrated, and they should be used with caution in high-risk patients or with other drugs that in¯uence renal or cardiovascular hñmodynamics . COX-2 selective inhibitors are contraindicated in the presence of an active peptic . prophylactic use of aspirin should not be removed when COX-2 selective . acetaminophen is available when in¯ammation is not the foremost issue in pain management and remains the ®rst choice analgesic for mild to moderate . opioids can improve the quality of life of patients in pain, but their use requires particular precautions, both when choosing the speci®c opioid and singling out . the risk of opioid addiction can be reduced by avoiding their prescription in pain syndromes that are poorly responsive to opioids, such as psychogenic or neuropathic pain, and by selecting an opioid with a good pharmacokinetic and . the risk can be minimized by prescribing opioids to patients with a history of drug abuse only with great caution and under strict medical supervision. To reduce the risk even further see the recommendations in .
. oral formulations, slow-release formulations, or even a drug whose opiate component necessitates bioactivation, such as codeine or tramadol, should be . there is evidence that anti-depressants have analgesic properties in chronic pain . non-selective tricyclics remain the most e€ective Advances in pain relief for spinal disorders 119 . epidemiological studies to evaluate the prevalence and incidence of the di€erent pain components in common chronic back pain are needed . experimental studies are needed to evaluate the importance of `central sensitization' in chronic back pain.
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