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 eect 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 ecacy, 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±6942/02/01010517 $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 dicult 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 oers a new target for pain modulation in
chronic pain patients. Persistent pain syndromes oer no biological advantage and lead
to profound biological alterations in both the peripheral and central nervous systems
with a potential `central sensitization' and suering.Furthermore, persistent pain
profoundly aects 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 aerent ®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 insuciently 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
ofadverseeects 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 dicult.
Single-dose analgesic trials using reproducible clinical procedures (dental extraction,
post-surgical, or post-partum models) are not sucient to assess their value in clinical
practice, although such trials may be helpful in determining the relative ecacy of
NSAIDs. Eective 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 eective NSAID than ibuprofen, they both showed the same level of ecacy
when the dosage was adjusted, i.e. 50 mg of diclofenac orally was no more ecient
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 eective 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 ecacy and tolerability of NSAIDs in ankylosing spondylitis.
Evidence of long-term ecacy 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 eects and are eective 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 ecacy 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 ecacy 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) suering 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 eects 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 dier 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 eecThese adverse eects 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 eects. 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) 2.1) with a greater increase when patients had a history of heart disease
(OR 10.5) compared to those (OR 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 dierence in cardiovascular events is that there is a protective eect
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 aected 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 eect 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 ecacyThis centrally acting
analgesic is devoid of the gastric or renal adverse event pro®le usually seen with
NSAIDs. Acetaminophen is as eective 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 eective 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 eectively 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 ecacy 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 diculty 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 eective 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 dierentiated 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 diculties 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 insucient 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 eects, 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
eects 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 eects could also be mediated through an involvement
in the opioidergic system. ADs have additional eects on various ion channels such as
inhibition of cardiac or neuronal Na channels. This latter blockade could be involved
in the analgesic eects of ADs. Some authors have claimed that the analgesic eect of
ADs could be an epiphenomenon of their sedative eects. Meta-analysis has shown
that non-sedative ADs are as eective 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 eects 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 ecacy 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 dierences 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 suering from chronic BP referred to primary practice,
nortriptyline and maprotiline showed an analgesic eect 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 eect 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
eects. 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 ecacy of tricyclics compared to These
conclusions were con®rmed in meta-analyses and non-selective tricyclics remain the
most eective. Several dose±response studies in patients did not produce consistent
®ndings regarding the relationship between dose, serum levels and analgesic eect.
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 ineciency after an adequate period of treatment. ADs are associated with a
relatively high incidence of adverse eects in therapeutic usage. Many of the commonly
observed adverse eects, such as dryness of mouth, blurred vision and drowsiness can
be troublesome particularly at the start of tricyclic treatment. Studies have shown
higher adverse eect scores at the start of treatment than 4±6 weeks later. The most
common cardiovascular adverse eect 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 eects and beliefs about adverse eects are major
determinants of non-compliance in patient populations suering from a variety of
diseases or problems. Occurrence and severity of adverse eects 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 suering
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 eects
For ADs, a fear of adverse eects 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 eects and raise a greater fear of losing contrHowever, a patient's
attention to adverse eects 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 eects. Adverse
eects 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 suering 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 dierences.
Apart from depression, CBPs' description of the indications for ADs included mood
improvement, soothing eects, 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 eects 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 aect their pain problem. The eect 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 diculties 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 eects 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
suering.Even when ADs are prescribed because of their analgesic eect, 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 diculties 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 dierentiate 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 eects (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 dicult to suppress. Persistent pain syndromes oer 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 dierent
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 dierent when one takes into account the long
Indeed, in terms of ecacy, 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 aected 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
eectively 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 oer bene®ts in chronic pain: meta-analyses have con®rmed that non-
selective tricyclics remain the most eective 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
aect it. The analgesic eect of anti-depressants is barely known, whereas the adverse
eects 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 ecacy, 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 aected 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 eective
Advances in pain relief for spinal disorders 119
. epidemiological studies to evaluate the prevalence and incidence of the dierent
pain components in common chronic back pain are needed
. experimental studies are needed to evaluate the importance of `central
sensitization' in chronic back pain.
. prospective longitudinal studies to evaluate the ecacy and the incidence of renal
and cardiovascular incidents related to NSAIDs versus acetaminophen or opioids
. prospective longitudinal studies to evaluate the ecacy and the safety of dierent
. further studies are needed to investigate the dose response/eect of anti-
depressants on chronic back pain and the in¯uence of the neuropathic pain
1. Ossipov MH, Lai J, Malan TP Jr & Porreca F. Spinal and supraspinal mechanisms of neuropathic pain.
Annals of the New York Academy of Science 2000; 909: 12±24.
2. Woolf CJ & Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet
3. Anonymous. Drug treatment of neuropathic pain. Drug Therapeutic Bulletin 2000; 38: 89±93.
4. AllazAF, Vannotti M, Desmeules J et al. Use of the label `litigation neurosis' in patients with somatoform
pain disorder. General Hospital Psychiatry 1998; 20: 91±97.
5. Woolf CJ & Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000; 288: 1765±1769.
6. Perrot S & Guilbaud G. Pathophysiology of joint pain. Revue du Rhumatisme (English edn) 1996; 63:
7. Ashburn MA & Staats PS. Management of chronic pain. Lancet 1999; 353: 1865±1869.
8. Besson J-M. The neurobiology of pain. Lancet 1999; 353: 1610±1615.
9. Anonymous. Cancer Pain Relief and Palliative Care. Geneva: WHO Guidelines, 1996.
10. Furlan AD, Clarke J, Esmail R et al. Critical review of reviews on the treatment of chronic low back pain.
11. McQuay HJ. In McQuay HJ & Moore RA (eds), In: An evidence-based Resource for Pain Relief. pp 1±13.
12. McQuay HJ. Oral ibuprofen and diclofenac in postoperative pain. In McQuay HJ & Moore RA (eds) An
Evidence-based Resource for Pain Relief, pp 78±83. Oxford: Oxford University Press, 1998.
13. Van Tulder MW, Scholten RJ, Koes BW & Deyo RA. Nonsteroidal anti-in¯ammatory drugs for low back
pain: a systematic review within the framework of the Cochrane collaboration back review group. Spine
14. Dougados M, Gueguen A, Nakache JP et al. Ankylosing spondylitis: what is the optimum duration of a
clinical study? A one year versus a 6 weeks non-steroidal anti-in¯ammatory drug trial. Rheumatology 1999;
15. Silverstein FE, Faich G, Goldstein JL et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-
in¯ammatory drugs for osteoarthritis and rheumatoid arthritis. The CLASS study: a randomized
controlled trial. Celecoxib Long-term Arthritis Safety Study. Journal of the American Medical Association
16. Bombardier C, Laine L, Reicin A et al and VIGOR Study Group. Comparison of upper gastrointestinal
toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. New England Journal of Medicine
17. Cannon GW & Breedveld FC. Ecacy of cyclooxygenase-2-speci®c inhibitors. American Journal of
Medicine 2001; 110 (supplement 1): 6±12.
18. Pohjolainen T, Jekunen A, Autio L & Vuorela H. Treatment of acute low back pain with the COX-2-
selective anti-in¯ammatory drug nimesulide: results of a randomized, double-blind comparative trial
versus ibuprofen. Spine 2000; 25: 1579±1585.
19. Dougados M, Behier JM, Jolchine I et al. Ecacy of celecoxib, a cyclooxygenase 2-speci®c inhibitor, in the
treatment of ankylosing spondylitis: a six-week controlled study with comparison against placebo and
against a conventional nonsteroidal antiin¯ammatory drug. Arthritis and Rheumatism 2001; 44: 180±185.
20. Van Steenbergen W, Peeters P, De Bondt J et al. Nimesulide-induced acute hepatitis: evidence from six
cases. Journal of Hepatology 1998; 29: 135±141.
21. Whelton A, Maurath CJ, Verburg KM & Geis GS. Renal safety and tolerability of celecoxib, a novel
cyclooxygenase-2 inhibitor. American Journal of Therapeutics 2000; 7: 159±175.
22. Brater DC, Harris C, Redfern JS & GertzBJ. Renal eects of cox-2-selective inhibitors. American Journal
23. Page J & Henry D. Consumption of NSAIDs and the development of congestive heart failure in elderly
patients: an underrecognized public health problem. Archives of Internal Medicine 2000; 160: 777±784.
24. Committee on safety medicine. Current Problems in Pharmacovigilance 2000; 26: 13.
25. Flower RJ & Vane JR. Inhibition of prostaglandin synthetase in brain explains the antipyretic activity of
acetaminophen. Nature 1972; 240: 410±411.
26. Tolman EL, Fuller BL, Marignan BA et al. Tissue selectivity and variability of eect of acetaminophen on
arachidonic acid metabolism. Prostaglandins Leukotrien Medicine 1983; 12: 347±356.
27. Ferrari RA, Ward SJ & Zobre CM. Estimation of the in vivo cyclooxygenase inhibitors on prostaglandin
E2 levels in mouse brain. European Journal of Pharmacology 1990; 179: 25±34.
28. Carlsson KH & Jurna I. Central analgesic eect of paracetamol manifested by depression of nociceptive
activity in thalamic neurones of the rat. Neuroscience Letters 1987; 77: 339±343.
29. Ferreira SH, Lorenzetti BB & Correa FMA. Central and peripheral antialgesic action of aspirin-like drugs.
European Journal of Pharmacology 1978; 53: 39±48.
30. Tjolsen A, Lund A & Hole K. Antinociceptive eect of paracetamol in rats is partly dependent on spinal
serotoninergic systems. European Journal of Pharmacology 1991; 193: 193±201.
31. Piletta P, Porchet H & Dayer P. Central analgesic eect of acetaminophen but not of aspirin. Clinical
Pharmacology and Therapeutics 1991; 41: 350±354.
32. Pelissier T, Alloui A, Paeile C & Eschalier A. Evidence of central antinociceptive eect of paracetamol
involving spinal 5HT3 receptors. Neuroreport (England) 1995; 6: 1546±1548.
33. Schnitzer TJ. Non-NSAID pharmacologic treatment options for the management of chronic pain.
American Journal of Medicine 1998; 105: 45S±52S.
34. Ray WA, Stein MC, Byrd V et al. Educational program for physicians to reduce use of non-steroidal anti-
in¯ammatory drugs among community-dwelling elderly persons: a randomized controlled trial. Medical
35. Bannwarth B. Risk-bene®t assesment of opioids in chronic noncancer pain. Drug Safety 1999; 283±296.
36. Federation of State Medical Boards of the US. Model Guidelines for the Use of Controlled Substances for the
Treatment of Pain. Euless: Federation of State Medical Boards of the United States, Inc, 1998.
37. Dellimijn P, van Duijn H & Vanneste J. Prolonged treatment with transdermal fentanyl in neuropathic
pain. Journal of Pain and Symptom Management 1998; 16: 220±229.
38. Jamison RN, Raymond SA, Slawsby EA et al. Opioid therapy for chronic noncancer back pain. A
randomized prospective study. Spine 1998; 23: 2591±2600.
39. Schnitzer TJ, Gray WL, Paster RZ & Kamin M. Ecacy of tramadol in treatment of chronic low back
pain. Journal of Rheumatology 2000; 27: 772±778.
40. Schnitzer TJ, Kamin M & Olson WH. Tramadol allows reduction of naproxen dose among patients with
naproxen-responsive osteoarthritis pain: a randomized, double-blind, placebo-controlled study. Arthritis
and Rheumatism 1999; 42: 1370±1377.
41. Schoerman J. Long-term opioid analgesic therapy for severe refractory lumbar spine pain. Clinical
42. Buskila D. Drug therapy. Bailliere's Best Practice Research in Clininical Rheumatology 1999; 13: 479±485.
43. WHO, New Guidelines to Evaluate National Opioid Policy. 2001; 14: 1.
44. Joranson DE, Ryan KM, Gilson AM & Dahl JL. Trends in medical use and abuse of opioid analgesics.
Journal of the American Medical Association 2000; 283: 1710±1714.
45. Perrot S, Bannwarth B, Bertin P et al. Use of morphine in nonmalignant joint pain: the Limoges
recommendations. The French Society for Rheumatology. Revue of Rheumatology (English Edition) 1999;
46. McQuay HJ, Tramer M, Nye BA et al. A systematic review of antidepressants in neuropathic pain. Pain
47. Fishbain D. Evidenced-based data on pain relief with antidepressants. Annals of Medicine 2000; 32:
48. Ansari A. The ecacy of newer antidepressants in the treatment of chronic pain: a review of current
literature. Harward Review of Psychiatry 2000; 7: 257±277.
Advances in pain relief for spinal disorders 121
49. Tatsumi M, Groshan K, Blakely RD & Richelson E. Pharmacological pro®le of antidepressants and related
compounds at human monoamine transporters. European Journal of Pharmacology 1997; 340: 249±258.
50. Atkinson JH, Slater MA, Williams RA et al. A placebo-controlled randomized clinical trial of
nortriptyline from chronic low back pain. pain 1998; 76: 287±296.
51. Max MB. Antidepressant drugs as treatments for chronic pain: ecacy and mechanisms. In Bromm B &
Desmedt JE (eds) Pain and the Brain: from Nociception to Cognition. Advances in Pain Research and Therapy,
vol 22, pp 501±515. New York: Raven Press, 1995.
52. Nutt D. Substance-P antagonists: a new treatment for depression? Lancet 1998; 352: 1644±1645.
53. Max MB, Schafer SC, Culnane M et al. Amitriptyline, but not lorazepam, relieves postherpetic neuralgia.
54. Turner JA & Denny C. Do antidepressant medications relieve chronic low back pain? Journal of Family
55. Sindrup SH, Gram LF, Brosen K et al. The selective reuptake serotonin inhibitor paroxetine is eective
in the treatment of diabetic neuropathy symptoms. Pain 1990; 42: 135±144.
56. Haynes RB, Taylors DW & Sackett DL. Compliance in Health Care. London: Hopkins Press, 1979.
57. Kouyanou K, Pither CE & Wessely S. Medication misuse, abuse and dependence in chronic pain patients.
Journal of Psychosomatic Research 1997; 43: 497±504.
58. Ferrari A, Stefani M, Sternieri S et al. Analgesic drug taking: beliefs and behavior among headache
patients. Headache 1997; 37: 88±94.
59. Brus H, van de Laar M, Taal E et al. Compliance in rheumatoid arthritis and the role of formal patient
education. Seminars in Arthritis and Rheumatism 1997; 26: 702±710.
60. De Klerk E & van der Linden SJ. Compliance monitoring of NSAID drug therapy in ankylosing
spondylitis experiences with an electronic monitoring device. British Journal of Rheumatology 1996; 35:
61. Nordin M, Cedraschi C & Skovron ML. Patient-health care provider relationship in patients with non-
speci®c low back pain: a review of some problem situations. BaillieÁre's Clinical Rheumatology 1998; 12:
62. McGregor EA. The doctor and the migraine patient: improving compliance. Neurology 1997; 48: S16±S20.
63. Donovan JL & Blake DR. Patient non-compliance. Deviance or reasoned decision-making? Social Sciences
64. Benkert O, Graf-Morgenstern M, Hillert A et al. Public opinion on psychotropic drugs: an analysis of the
factors in¯uencing acceptance or rejection. Journal of Nerve and Mental Disease 1997; 185: 51±58.
65. Wynne HA & Long A. Patient awareness for the adverse eects of non-steroidal anti-in¯ammatory drugs
(NSAIDs). British Journal of Clinical Pharmacology 1996; 42: 253±256.
66. Cedraschi C, Piguet V, Fischer W et al. Beliefs about antidepressants in back pain patients: a clue to non-
compliance. The Annual Meeting of the International Society for the Study of the Lumbar Spine. AdelaõÈde,
67. Cedraschi C, Piguet V, Fischer W et al. Patient information lea¯ets and antidepressant prescription in
chronic pain patients. Proceedings of the 9th World Congress on Pain. In Devor M, Rowbotham M &
Wiesenfeld-Hallin Z (eds) Progress in Pain Research and Management, vol 16, pp 887±895. Seattle: IASP,
68. Piguet V, Cedraschi C, Fischer W et al. Antidepressants representations in chronic pain patientsThe 9th
World Congress on Pain, Vienna. p. 471 Vienna, 1999 (Abstract).
69. Fischer W, Goerg D, Zbinden E & GuimoÂn J. Determining factors and the eects of attitudes towards
psychotropic medication. In Guimon J, Fischer W & Sartorius N (eds) The Image of Madness. The Public
Facing Mental Illness and Psychiatric Treatment, pp 162±186. Basel: Karger, 1999.
Cub@: Medio ambiente y Desarrollo; Revista electrónica de la Agencia de Medio Ambiente Responsabilidad civil y licencia ambiental. Instrumentos al servicio del desarrollo sostenible.¹ Civil responsibility and environmental license. Instruments to the service of the sustainable development Autor: Lic. Daimar Cánovas González Asesor jurídico Instituto de Geografía Tropical Resumen
“Product Management and Development for Insurance Companies” 4th – 6th June 2009 | Zagreb / Croatia organised by the European Actuarial Academy in cooperation with the Croatian Society of Actuaries. provisional programm 1. Introduction Product management in the European Insurance Industry is one of the most important – if not only – tools for insurance compani