Download Antidepressants in the treatment of neuropathic pain.

Trends Pharmacol Sci. 2006 Jul;27(7):348-54.
Antidepressants and pain.
Micó JA, Ardid D, Berrocoso E, Eschalier A.
Pharmacology and Neuroscience Research Group, Department of
Neuroscience (Pharmacology and Psychiatry), School of Medicine, University of
Cádiz, Plaza Fragela 9, 11003 Cádiz, Spain. [email protected]
Abstract
Tricyclic antidepressants, together with anticonvulsants, are considered to be
first-line drugs for the treatment of neuropathic pain. Antidepressants are
analgesic in patients with chronic pain and no concomitant depression,
indicating that the analgesic and antidepressant effects occur independently.
The analgesia induced by these drugs seems to be centrally mediated but
consistent evidence also indicates a peripheral site of action. Several
pharmacological mechanisms account for their antinociceptive effect but the
inhibition of monoamine transporters (and, consequently, the facilitation of
descending inhibition pain systems) is implicated on the basis of mechanistic
and knockout-mouse studies. However, pain is a common symptom of
depression, and depression is frequent in chronic pain patients, supporting the
hypothesis that pain and depression share some common biochemical
mechanisms. We suggest that antidepressants have a genuine analgesic effect
and that research into their mechanisms of action will help to facilitate the
development of new drugs.
Basic Clin Pharmacol Toxicol. 2005 Jun;96(6):399-409.
Antidepressants in the treatment of neuropathic pain.
Sindrup SH, Otto M, Finnerup NB, Jensen TS.
Department of Neurology, Odense University Hospital, DK-5000 Odense,
Denmark. [email protected]
Abstract
Neuropathic pain is due to lesion or dysfunction of the peripheral or central
nervous system. Tricyclic antidepressants and anticonvulsants have long been
the mainstay of treatment of this type of pain. Tricyclic antidepressants may
relieve neuropathic pain by their unique ability to inhibit presynaptic reuptake of
the biogenic amines serotonin and noradrenaline, but other mechanisms such
as N-methyl-D-aspartate receptor and ion channel blockade probably also play
a role in their pain-relieving effect. The effect of tricyclic antidepressants in
neuropathic pain in man has been demonstrated in numerous randomised,
controlled trials, and a few trials have shown that serotonin noradrenaline and
selective serotonin reuptake inhibitor antidepressants also relieve neuropathic
pain although with lower efficacy. Tricyclic antidepressants will relieve one in
every 2-3 patients with peripheral neuropathic pain, serotonin noradrenaline
reuptake inhibitors one in every 4-5 and selective serotonin reuptake inhibitors
one in every 7 patients. Thus, based on efficacy measures such as numbers
needed to treat, tricyclic antidepressants tend to work better than the
anticonvulsant gabapentin and treatment options such as tramadol and
oxycodone, whereas the serotonin noradrenaline reuptake inhibitor venlafaxine
appears to be equally effective with these drugs and selective serotonin
reuptake inhibitors apparently have lower efficacy. Head-to-head comparisons
between antidepressants and the other analgesics are lacking.
Contraindications towards the use of tricyclic antidepressants and low
tolerability in general of this drug class--may among the antidepressants--favour
the use of the serotonin noradrenaline reuptake inhibitors. A recent study on
bupropion, which is a noradrenaline and dopamine uptake inhibitor, indicated a
surprisingly high efficacy of this drug in peripheral neuropathic pain. In
conclusion, antidepressants represent useful tools in neuropathic pain treatment
and must still be considered as first line treatments of neuropathic pain.
However, without head-to-head comparisons between antidepressants and
other analgesics, it is not possible to provide real evidence-based treatment
algorithms for neuropathic pain.
Adv Psychosom Med. 2011;30:125-38. Epub 2011 Apr 19.
Cannabinoids for pain management.
Thaler A, Gupta A, Cohen SP.
Pain Management Division, Department of Anesthesiology, University of
Pennsylvania School of Medicine, Philadelphia, PA 21029, USA.
Abstract
Cannabinoids have been used for thousands of years to provide relief from
suffering, but only recently have they been critically evaluated in clinical trials.
This review provides an in-depth examination of the evidence supporting
cannabinoids in various pain states, along with an overview of potential adverse
effects. In summary, there is strong evidence for a moderate analgesic effect in
peripheral neuropathic and central pain conditions, and conflicting evidence for
their use in nociceptive pain. For spasticity, most controlled studies demonstrate
significant improvement. Adverse effects are not uncommon with cannabinoids,
though most are not serious and self-limiting. In view of the limited effect size
and low but not inconsequential risk of serious adverse events, cannabinoids
should be employed as analgesics only when safer and more effective
medication trials have failed, or as part of a multimodal treatment regimen.
Top Curr Chem. 2011;299:29-62.
Opioids in preclinical and clinical trials.
Nagase H, Fujii H.
School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo,
Japan. [email protected]
Abstract
Since 1952, when Gates determined the stereo structure of morphine,
numerous groups have focused on discovering a nonnarcotic opioid drug.
Although several natural, semisynthetic, and synthetic opioid ligands (alkaloids
and peptides) have been developed in clinical studies, very few were
nonnarcotic opioid drugs. One of the most important studies in the opioid field
appeared in 1976, when Martin and colleagues established types of opioid
receptors (these are now classified into mu, delta, and kappa types). Later,
Portoghese discovered a highly selective mu type opioid receptor antagonist,
beta-funaltrexamine. This led to the finding that the mu type opioid receptor was
correlated to drug dependence. Consequently, delta, and particularly kappa,
opioid agonists were expected to lead to ideal opioid drugs. Moreover, opioid
antagonists were evaluated for the treatment of symptoms related to
undesirable opioid system activation. In this chapter, we pro
J Fam Pract. 2011 May;60(5):288-9.
Clinical inquiries. What are the adverse effects of prolonged opioid use in
patients with chronic pain?
Edgerton L, Loven B.
New Hanover Regional, Medical Center Residency in Family Medicine,
Wilmington, NC, USA.
Adv Psychosom Med. 2011;30:139-61.
Ketamine in pain management.
Cohen SP, Liao W, Gupta A, Plunkett A.
Pain Management Division, Department of Anesthesiology and Critical Care
Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21029, USA.
[email protected]
Abstract
Ketamine is an N-methyl-D-aspartate receptor antagonist that has been in
clinical use in the USA for over 30 years. Its ability to provide profound
analgesia and amnesia while maintaining spontaneous respiration makes it an
ideal medication for procedure-related pain and trauma. In the chronic pain
arena, its use continues to evolve. There is strong evidence to support its short-
term use for neuropathic and nociceptive pain, and conflicting evidence for
preemptive analgesia. Its potential ability to prevent 'windup' and, possibly,
'reboot' aberrant neurologic pathways in neuropathic and central pain states has
generated intense interest. However, the long-term use of ketamine for chronic
neuropathic pain is limited by its side effect profile, and is largely anecdotal.
More research is needed to better ascertain its long-term efficacy and side
effects, to determine the ideal candidates for sustained treatment and to
develop means of exploiting the antinociceptive properties of ketamine while
minimizing the adverse effects.
Adv Psychosom Med. 2011;30:61-91.
Opioid therapy in patients with chronic noncancer pain: diagnostic and
clinical challenges.
Cheatle MD, O'Brien CP.
Center for Studies of Addiction, Department of Psychiatry, University of
Pennsylvania, Philadelphia, PA 19104, USA. [email protected]
Abstract
Chronic opioid therapy for patients with chronic noncancer pain has become
controversial, given the rising prevalence of opioid abuse. The prevailing
literature suggests that the rate of addiction in chronic noncancer pain patients
exposed to opioid therapy is relatively low, especially in those patients without
significant concomitant psychiatric disorders and personal and family history of
addiction. However, the escalating rate of misuse of prescription opioids has
resulted in many clinicians caring for these patients to be more judicious in
prescribing opioids. Accurately diagnos ing addiction in chronic pain patients
receiving opioids is complex. Managing the patient with pain and co-occurring
opioid abuse is equally challenging. Diagnostic issues, current guidelines for the
appropriate use of opioids in the chronic pain population and risk stratification
models are examined. Pharmacologic and nonpharmacologic treatment
strategies for the patient with pain and opioid addiction are reviewed.
Adv Psychosom Med. 2011;30:22-60. Epub 2011 Apr 19.
Addiction and brain reward and antireward pathways.
Gardner EL.
Neuropsychopharmacology Section, Intramural Research Program, National
Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224,
USA. [email protected]
Abstract
Addictive drugs have in common that they are voluntarily self-administered by
laboratory animals (usually avidly), and that they enhance the functioning of the
reward circuitry of the brain (producing the 'high' that the drug user seeks). The
core reward circuitry consists of an 'in-series' circuit linking the ventral
tegmental area, nucleus accumbens and ventral pallidum via the medial
forebrain bundle. Although originally believed to simply encode the set point of
hedonic tone, these circuits are now believed to be functionally far more
complex, also encoding attention, expectancy of reward, disconfirmation of
reward expectancy, and incentive motivation. 'Hedonic dysregulation' within
these circuits may lead to addiction. The 'second-stage' dopaminergic
component in this reward circuitry is the crucial addictive-drug-sensitive
component. All addictive drugs have in common that they enhance (directly or
indirectly or even transsynaptically) dop-aminergic reward synaptic function in
the nucleus accumbens. Drug self-administration is regulated by nucleus
accumbens dopamine levels, and is done to keep nucleus accumbens
dopamine within a specific elevated range (to maintain a desired hedonic level).
For some classes of addictive drugs (e.g. opiates), tolerance to the euphoric
effects develops with chronic use. Postuse dysphoria then comes to dominate
reward circuit hedonic tone, and addicts no longer use drugs to get high, but
simply to get back to normal ('get straight'). The brain circuits mediating the
pleasurable effects of addictive drugs are anatomically, neurophysiologically
and neurochemically different from those mediating physical dependence, and
from those mediating craving and relapse. There are important genetic
variations in vulnerability to drug addiction, yet environmental factors such as
stress and social defeat also alter brain-reward mechanisms in such a manner
as to impart vulnerability to addiction. In short, the 'bio-psycho-social' model of
etiology holds very well for addiction. Addiction appears to correlate with a
hypodopaminergic dysfunctional state within the reward circuitry of the brain.
Neuroimaging studies in humans add credence to this hypothesis. Credible
evidence also implicates serotonergic, opioid, endocannabinoid, GABAergic
and glutamatergic mechanisms in addiction. Critically, drug addiction
progresses from occasional recreational use to impulsive use to habitual
compulsive use. This correlates with a progression from reward-driven to habitdriven drug-seeking behavior. This behavioral progression correlates with a
neuroanatomical progression from ventral striatal (nucleus accumbens) to
dorsal striatal control over drug-seeking behavior. The three classical sets of
craving and relapse triggers are (a) reexposure to addictive drugs, (b) stress,
and (c) reexposure to environmental cues (people, places, things) previously
associated with drug-taking behavior. Drug-triggered relapse involves the
nucleus accumbens and the neurotransmitter dopamine. Stress-triggered
relapse involves (a) the central nucleus of the amygdala, the bed nucleus of the
stria terminalis, and the neurotransmitter corticotrophin-releasing factor, and (b)
the lateral tegmental noradrenergic nuclei of the brain stem and the
neurotransmitter norepinephrine. Cue-triggered relapse involves the basolateral
nucleus of the amygdala, the hippocampus and the neurotransmitter glutamate.
Knowledge of the neuroanatomy, neurophysiology, neurochemistry and
neuropharmacology of addictive drug action in the brain is currently producing a
variety of strategies for pharmacotherapeutic treatment of drug addiction, some
of which appear promising.
Postgrad Med. 2011 Mar;123(2):119-30.
Pain management in primary care: strategies to mitigate opioid misuse,
abuse, and diversion.
McCarberg BH.
Chronic Pain Management Program, Kaiser Permanente, San Diego, CA, USA.
[email protected]
Abstract
Pain is among the most common reasons patients seek medical attention, and
the care of patients with pain is a significant problem in the United States. Acute
pain (mild-to-moderate intensity) represents one of the most frequent
complaints encountered by primary care physicians (PCPs) and accounts for
nearly half of patient visits. However, the overall quality of pain management
remains unacceptable for millions of US patients with acute or chronic pain, and
underrecognition and undertreatment of pain are of particular concern in
primary care. Primary care physicians face dual challenges from the emerging
epidemics of undertreated pain and prescription opioid abuse. Negative impacts
of untreated pain on patient activities of daily living and public health
expenditures, combined with the success of opioid analgesics in treating pain
provide a strong rationale for PCPs to learn best practices for pain
management. These clinicians must address the challenge of maintaining
therapeutic access for patients with a legitimate medical need for opioids, while
simultaneously minimizing the risk of abuse and addiction. Safe and effective
pain management requires clinical skill and knowledge of the principles of
opioid treatment as well as the effective assessment of risks associated with
opioid abuse, addiction, and diversion. Easily implementable patient selection
and screening, with selective use of safeguards, can mitigate potential risks of
opioids in the busy primary practice setting. Primary care physicians can
become advocates for proper pain management and ensure that all patients
with pain are treated appropriately.
J Fam Pract. 2011 Apr;60(4):206-12.
Opioids for osteoarthritis? Weighing benefits and risks: a Cochrane
Musculoskeletal Group review.
Howes F, Buchbinder R, Winzenberg TB.
Menzies Research Institute Tasmania, University of Tasmania, Hobart,
Tasmania, Australia. [email protected]
Abstract
Untreated pain is a major public health problem, but concerns about opioid
misuse remain. This evidence-based look at when--or whether--opioids are
indicated for OA patients will help you achieve the right balance.
J Pediatr Hematol Oncol. 2011 Apr;33 Suppl 1:S6-S11.
Choice of opioids and the WHO Ladder.
Glare P.
Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York
Avenue, New York, NY 10065, USA. [email protected]
Abstract
Physicians in developing countries who start to develop new, palliative care
services face real barriers because of opiophobia in their countries. These
physicians need to convince their colleagues in their own institutions about the
need to adopt clear policies concerning pain management and palliative care in
general. Moreover, these physicians need to explain the importance of such
new services to their administrators and often legislators at the national level.
People in the Middle East are facing cultural, traditional, and religious obstacles
with regard to the introduction of opioids into regular use both in hospitals and in
the community. In many countries, these drugs are believed to be drugs of
addiction and in some cases, even dangerous drugs. Our goal is to enhance the
establishment of pain units, being it within the framework of the Oncology
Center, Palliative Care Services, or as stand-alone units.
J Opioid Manag. 2011 Jan-Feb;7(1):69-79.
Opioid delivery in the treatment of cancer breakthrough pain: a review of
routes of administration.
Nicholson B, Agarwala SS.
Division of Pain Medicine, Pain Specialists of Greater Lehigh Valley,
Pennsylvania, USA.
Abstract
Analgesics delivered via the oral route of administration (capsules, tablets, or
solutions) are most commonly used to treat cancer breakthrough pain (BTP);
however, the effectiveness of oral opioids may be limited by slow
gastrointestinal absorption and first-pass metabolic effects. Although the
limitations presented by oral opioid delivery are acknowledged and formulations
and delivery systems that mirror the temporal characteristics of the majority of
cancer BTP episodes are available, short-acting oral opioids are the accepted
standard of care. The purpose of this review is to provide an overview of the
different routes of opioid administration used in the treatment of cancer BTP
and briefly discuss the characteristics of different delivery systems.
J Opioid Manag. 2011 Jan-Feb;7(1):35-45.
A systematic
problems.
compilation of reports published on opioid-related
Butts M, Jatoi A.
Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Abstract
OBJECTIVES:
This study examined the published literature on case reports of opioid-related
problems to create a compendium that might lead to greater awareness and
fewer such events.
METHODS:
PubMed, Ovid, and the Cumulative Index to Nursing and Allied Health Literature
were searched for case reports. A problem was defined as a healthcare
provider's or patient's administration of an opioid in an unintended manner
resulting in harm.
RESULTS:
From more than 2200+ unique articles, 104 met the inclusion criteria. Fentanyl
was most implicated. Problems included pump programming errors, patients'
chewing transdermal patches, and pediatric overdosing with an oral droplet
dispenser. Of 105 articles, 19 focused on patients with cancer and 86 on
patients without cancer.
CONCLUSIONS:
This compendium of opioid-related problems might generate further discussion
about how best to reduce their number and morbidity.
Drug Ther Bull. 2011 Feb;49(2):18-21; quiz i-ii.
Reducing NSAID-induced gastrointestinal complications.
Abstract
Around 17 million items for non-steroidal anti-inflammatory drugs (NSAIDs) are
prescribed annually in England alone.1 These drugs are associated with upper
gastrointestinal complications.2 For example, each year, NSAIDs cause about
3,500 hospitalisations for, and 400 deaths from, ulcer bleeding in people aged
60 years or above.3 Aspirin, even in low doses, is also associated with
gastrointestinal complications.4 5 Here we assess strategies for reducing
gastrointestinal complications induced by NSAIDs, including aspirin and
selective inhibitors of cyclo-oxygenase-2 (coxibs).
Br J Anaesth. 2011 Mar;106(3):292-7.
Paracetamol and selective and non-selective non-steroidal antiinflammatory drugs for the reduction in morphine-related side-effects
after major surgery: a systematic review.
Maund E, McDaid C, Rice S, Wright K, Jenkins B, Woolacott N.
Centre for Reviews and Dissemination, University of York, York YO10 5DD, UK.
[email protected]
Abstract
Non-opioid analgesics, paracetamol, non-steroidal anti-inflammatory drugs
(NSAIDs), or cyclo-oxygenase 2 (COX-2) inhibitors are often given along with
morphine as part of multimodal analgesia after major surgery. We have
undertaken a systematic review and a mixed treatment comparison (MTC)
analysis in order to determine explicitly which class of non-opioid analgesic,
paracetamol, NSAIDs, or COX-2 inhibitors is the most effective in reducing
morphine consumption and morphine-related adverse effects. Sixty relevant
studies were identified. The MTC found that when paracetamol, NSAIDs, or
COX-2 inhibitors were added to patient-controlled analgesia (PCA) morphine,
there was a statistically significant reduction in morphine consumption:
paracetamol [mean difference (MD) -6.34 mg; 95% credibility interval (CrI) 9.02, -3.65], NSAIDs (MD -10.18; 95% CrI -11.65, -8.72), and COX-2 inhibitors
(MD -10.92; 95% CrI -12.77, -9.08). There was a significant reduction in nausea
and postoperative nausea and vomiting with NSAIDs compared with placebo
(odds ratio 0.70; 95% CrI 0.53, 0.88) but not for paracetamol or COX-2
inhibitors, nor for NSAIDs compared with paracetamol or COX-2 inhibitors.
There was no statistically significant difference in sedation between any
intervention and comparator. On the basis of six trials (n=695), 2.4% of
participants receiving an NSAID experienced surgical-related bleeding
compared with 0.4% with placebo. The MTC found that there is a decrease in
24 h morphine consumption when paracetamol, NSAID, or COX-2 inhibitors are
given in addition to PCA morphine after surgery, with no clear difference
between them. Similarly, the benefits in terms of reduction in morphine-related
adverse effects do not strongly favour one of the three non-opioid analgesics.
J Fam Pract. 2010 Nov;59(11):E1-6.
Which NSAID for your patient with osteoarthritis?
Scheiman JM, Sidote D.
University of Michigan Medical School, Ann Arbor, USA. [email protected]
Curr Med Res Opin. 2010 Dec;26(12):2871-6. Epub 2010 Nov 11.
New guidelines for topical NSAIDs in the osteoarthritis treatment
paradigm.
Altman RD.
David Geffen School of Medicine, University of California, Los Angeles, CA,
USA. [email protected]
Abstract
BACKGROUND:
Osteoarthritis (OA), the most common form of arthritis, often affects hands,
hips, and knees and involves an estimated 26.9 million US adults. Women have
a higher prevalence of OA, and the risk of developing OA increases with age,
obesity, and joint malalignment. OA typically presents with pain and reduced
function. Therapeutic programs are often multimodal and must take into account
pharmaceutical toxicities and patient comorbidities. For example, nonsteroidal
anti-inflammatory drugs (NSAIDs) are associated with cardiovascular,
gastrointestinal, and renal adverse events. Topical NSAIDs offer efficacy with
reduced systemic drug exposure.
RESEARCH DESIGN AND METHODS:
This is a review of current guideline recommendations regarding the use of
topical NSAIDs in OA of the hand and knee. Articles were identified by PubMed
search (January 1, 2000 to May 21, 2010).
RESULTS:
Several current guidelines for management of OA recommend topical NSAIDs,
indicating them as a safe and effective treatment. One guideline recommends
that topical NSAIDs be considered as first-line pharmacologic therapy. A US
guideline for knee OA recommends topical NSAIDs in older patients and in
patients with increased gastrointestinal risk.
CONCLUSIONS:
The consensus across US and European OA guidelines is that topical NSAIDs
are a safe and effective treatment for OA. Because the research base on topical
NSAIDs for OA is small, guidelines will continue to evolve.
Reumatismo. 2010 Jul-Sep;62(3):172-88.
Pain and ketoprofen: what is its role in clinical practice?
Sarzi-Puttini P, Atzeni F, Lanata L, Bagnasco M, Colombo M, Fischer F,
D'Imporzano M.
Source
Rheumatology Unit, L. Sacco University Hospital, Milan, Italy. [email protected]
Abstract
Ketoprofen is a drug belonging to the family of non-steroidal anti-inflammatory
drugs (NSAIDs). The present review examines the main available clinical
evidence of ketoprofen in the treatment of acute and chronic pain, of both
rheumatic and traumatic origin, as well as postoperative pain. Ketoprofen has
shown to be an excellent choice of drug for the treatment of chronic pain in
patients with osteoarthritis, rheumatoid arthritis or gout, demonstrating a high
level of efficacy with good tolerability also in elderly patients. Even in the
treatment of acute forms of pain such as bursitis, tendinitis and back pain,
ketoprofen compares favourably to other NSAIDs (e.g., ibuprofen and
diclofenac) in terms of efficacy. Ketoprofen has been shown to be effective also
for the treatment of post-operative pain, particularly in the orthopaedic field, with
an efficacy similar to opioids in some studies. In this setting, some evidence
indicates that ketoprofen exhibits additional important benefits, showing to be
effective in the prophylaxis of heterotopic calcification following hip or pelvic
major intervention, without affecting the bone healing process. Moreover, the
use of ketoprofen in elastomeric pump in combination with opioids or other
NSAIDs has proven to be effective and safe. In conclusion, available data
confirm that ketoprofen is effective and well tolerated, through different
administration
Intern Emerg Med. 2010 Oct;5 Suppl 1:S31-5.
Management of cancer pain.
Mercadante S.
Anesthesia and Intensive Care Unit, Pain Relief and Palliative Care Unit, La
Maddalena Cancer Center, Via San Lorenzo 312, 90146, Palermo, Italy.
[email protected]
Abstract
In the last decades, studies validating the WHO analgesic ladder have been
shown to have methodological limitations and different problems are unresolved
due to a lack of controlled studies on this subject. These problems include a
better definition of the role of NSAIDs, the prolonged use of NSAIDs in cancer
pain, and the utility of step 2. Moreover, the indications for using different strong
opioids and alternate routes of administration to improve pain relief in difficult
pain situations are not well established. The proportion of patients who do not
benefit from these treatments remain unclear, and how the opioid response may
be improved with the use of adjuvants is also uncertain. This review will offer an
update on these problems and the existing therapeutic opportunities.
Curr Med Chem. 2010;17(32):3769-805.
Selective COX-1 inhibition: A therapeutic target to be reconsidered.
Perrone MG, Scilimati A, Simone L, Vitale P.
Department of Medicinal Chemistry, University of Bari A. Moro, Via Orabona 4,
70125 (Bari), Italy.
Abstract
Since cyclooxygenase (COX) isozymes discovery, many papers and reviews
have been published to describe the structural bases of COX inhibition, and to
debate on the therapeutic and adverse effects of worldwide clinically used
nonsteroidal anti-inflammatory drugs (NSAIDs), included COX-2 selective
inhibitors (well known as Coxibs). COX-2 inhibition has been widely
investigated, whereas the role of COX-1 in human pathophysiology is mostly
not yet well ascertained. As time goes on, the cliché that the constitutively
expressed isoform COX-1 is only involved in normal physiological functions,
such as platelet aggregation, gastric mucosa protection and renal electrolyte
homeostasis is going to be shattered. Low-dose aspirin, behaving as a
preferential inhibitor of platelet COX-1, allowed to enlighten the role exerted by
this isoenzyme in many mammalian cell types. This review would elucidate the
most recent findings on selective COX-1 inhibition and their relevance to human
pathology such as cancer, neuro-inflammation, cardioprotection, fever and pain.
It would also focus on the design and development of new highly selective
COX-1 inhibitors, useful tools in pharmacological studies aimed at gaining a
deeper insight of the role of COX-1 in human health and disease. Among the
traditional NSAIDs, other then aspirin and indomethacin, only few examples of
selective COX-1 inhibitors (SC-560, FR122047, mofezolac, P6 and TFAP) have
been so far identified. This review has also the scope to stimulate the
development of novel drugs, which activity is COX-1 mediated.
Subcell Biochem. 2007;42:3-27.
Anti-inflammatory drugs in the 21st century.
Rainsford KD.
Biomedical Research Centre, Faculty of Health & Wellbeing, Sheffield Hallam
University, Howard Street, Sheffield, SI 1WB, UK. [email protected]
Abstract
Historically, anti-inflammatory drugs had their origins in the serendipitous
discovery of certain plants and their extracts being applied for the relief of pain,
fever and inflammation. When salicylates were discovered in the mid-19th
century to be the active components of Willow Spp., this enabled these
compounds to be synthesized and from this, acetyl-salicylic acid or Aspirin was
developed. Likewise, the chemical advances of the 19th-20th centuries lead to
development of the non-steroidal anti-inflammatory drugs (NSAIDs), most of
which were initially organic acids, but later non-acidic compounds were
discovered. There were two periods of NSAID drug discovery post-World War 2,
the period up to the 1970's which was the pre-prostaglandin period and
thereafter up to the latter part of the last century in which their effects on
prostaglandin production formed part of the screening in the drug-discovery
process. Those drugs developed up to the 1980-late 90's were largely
discovered empirically following screening for anti-inflammatory, analgesic and
antipyretic activities in laboratory animal models. Some were successfully
developed that showed low incidence of gastro-intestinal (GI) side effects (the
principal adverse reaction seen with NSAIDs) than seen with their predecessors
(e.g. aspirin, indomethacin, phenylbutazone); the GI reactions being detected
and screened out in animal assays. In the 1990's an important discovery was
made from elegant molecular and cellular biological studies that there are two
cyclo-oxygenase (COX) enzyme systems controlling the production of
prostanoids [prostaglandins (PGs) and thromboxane (TxA2)]; COX-1 that
produces PGs and TxA2 that regulate gastrointestinal, renal, vascular and other
physiological functions, and COX-2 that regulates production of PGs involved in
inflammation, pain and fever. The stage was set in the 1990's for the discovery
and development of drugs to selectively control COX-2 and spare the COX-1
that is central to physiological processes whose inhibition was considered a
major factor in development of adverse reactions, including those in the GI tract.
At the turn of this century, there was enormous commercial development
following the introduction of two new highly selective COX-2 inhibitors, known
as coxibs (celecoxib and rofecoxib) which were claimed to have low GI side
effects. While found to have fulfilled these aims in part, an alarming turn of
events took place in the late 2004 period when rofecoxib was withdrawn
worldwide because of serious cardiovascular events and other coxibs were
subsequently suspected to have this adverse reaction, although to a varying
degree. Major efforts are currently underway to discover why cardiovascular
reactions took place with coxibs, identify safer coxibs, as well as elucidate the
roles of COX-2 and COX-1 in cardiovascular diseases and stroke in the hope
that there may be some basis for developing newer agents (e.g. nitric oxidedonating NSAIDs) to control these conditions. The discovery of the COX
isoforms led to establishing their importance in many non-arthritic or non-pain
states where there is an inflammatory component to pathogenesis, including
cancer, Alzheimer's and other neurodegenerative diseases. The applications of
NSAIDs and the coxibs in the prevention and treatment of these conditions as
well as aspirin and other analogues in the prevention of thrombo-embolic
diseases now constitute one of the major therapeutic developments of the this
century. Moreover, new anti-inflammatory drugs are being discovered and
developed based on their effects on signal transduction and as anti-cytokine
agents and these drugs are now being heralded as the new therapies to control
those diseases where cytokines and other nonprostaglandin components of
chronic inflammatory and neurodegenerative diseases are manifest. To a lesser
extent safer application of corticosteroids and the applications of novel drug
delivery systems for use with these drugs as well as with NSAIDs also
represent newer technological developments of the 21st century. What started
out as drugs to control inflammation, pain and fever in the last two centuries
now has exploded to reveal an enormous range and type of anti-inflammatory
agents and discovery of new therapeutic targets to treat a whole range of
conditions that were never hitherto envisaged.
World J Gastroenterol. 2010 Dec 7;16(45):5651-61.
Non-steroidal anti-inflammatory drugs: What is the actual risk of liver
damage?
Bessone F.
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) constitute a family of drugs,
which taken as a group, represents one of the most frequently prescribed
around the world. Thus, not surprisingly NSAIDs, along with anti-infectious
agents, list on the top for causes of Drug-Induced Liver Injury (DILI). The
incidence of liver disease induced by NSAIDs reported in clinical studies is fairly
uniform ranging from 0.29/100 000 [95% confidence interval (CI): 0.17-051] to
9/100 000 (95% CI: 6-15). However, compared with these results, a higher risk
of liver-related hospitalizations was reported (3-23 per 100 000 patients).
NSAIDs exhibit a broad spectrum of liver damage ranging from asymptomatic,
transient, hyper-transaminasemia to fulminant hepatic failure. However, underreporting of asymptomatic, mild cases, as well as of those with transient livertests alteration, in conjunction with reports non-compliant with
pharmacovigilance criteria to ascertain DILI and flawed epidemiological studies,
jeopardize the chance to ascertain the actual risk of NSAIDs hepatotoxicity.
Several NSAIDs, namely bromfenac, ibufenac and benoxaprofen, have been
withdrawn from the market due to hepatotoxicity; others like nimesulide were
never marketed in some countries and withdrawn in others. Indeed, the
controversy concerning the actual risk of severe liver disease persists within
NSAIDs research. The present work intends (1) to provide a critical analysis of
the dissimilar results currently available in the literature concerning the
epidemiology of NSAIDS hepatotoxicity; and (2) to review the risk of
hepatotoxicity for each one of the most commonly employed compounds of the
NSAIDs family, based on past and recently published data.
Rev Med Interne. 2000 Nov;21(11):978-88.
[Non-steroidal anti-inflammatory agents with selective inhibitory activity
on cyclooxygenase-2. Interest and future prospects].
Blain H, Jouzeau JY, Netter P, Jeandel C.
Service de médecine interne C et gérontologie clinique, centre Antonin-Balmes,
CHU, Montpellier, France.
Abstract
INTRODUCTION: Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the
production of primary prostanoids by blocking the access of arachidonic acid to
the active site of the cyclooxygenases (COXs). Because the prostanoids
produced by COX-1 appear to play a physiological role (protection of the gastric
mucosa, platelet aggregation, vascular homeostasis, maintenance of renal
sodium-water balance) while those produced by COX-2 seem mainly to
intervene in the inflammatory response and in certain processes associated
with cell proliferation, the hypothesis has been put forward that the NSAIDs that
are selective COX-2 inhibitors should theoretically be capable of maintaining
NSAID therapeutic properties but also have fewer adverse side effects due to
the maintenance of prostaglandin production at normal physiological levels.
CURRENT KNOWLEDGE AND KEY POINTS: The hypothesis of COX
isoenzyme selectivity has led to a proposed classification for COX inhibitors: 1)
COX-1 selective inhibitors (low-dosage aspirin); 2) COX non-selective inhibitors
(the majority of classified NSAIDs, which when administered over the long term,
e.g., in cases of rheumatoid arthritis, cause duodenal ulcers in 20% of cases
and gastric hemorrhage in 1-4% of cases/year); 3) COX-2 preferential inhibitors
(meloxicam and nimesulide, which have fewer gastric side effects than standard
NSAIDs, but which are not risk-free at high doses); 4) COX-2 selective inhibitors
(celecoxib and rofecoxib). Preliminary clinical studies have shown that COX-2
selective inhibitors are as efficient as standard NSAIDs and have fewer adverse
digestive side effects, thereby confirming the interest of this proposed
classification. In the UK, the aforementioned studies have led to the
commercialization of rofecoxib for the treatment of pain and osteoarthritis, while
celecoxib has been introduced in medical practice in the USA and other
countries for the treatment of rheumatoid arthritis and osteoarthritis. FUTURE
PROSPECTS AND PROJECTS: Various epidemiological and laboratory studies
have indicated that NSAIDs may be able to reduce the risk of cancer (colorectal
cancer in particular) and Alzheimer's disease due to their inhibitory activity on
COXs, especially COX-2. The therapeutic contribution of COX-2 specific
inhibitors has to be more fully evaluated, particularly as these agents could
delay the healing of duodenal ulcers and interfere with several COX-2-induced
physiological functions. It is therefore suggested that until further information
becomes available, this new class of NSAIDs should be used with caution in
certain patient populations.
Gut. 2010 Dec;59(12):1670-9.
Effect of aspirin and NSAIDs on risk and survival from colorectal cancer.
Din FV, Theodoratou E, Farrington SM, Tenesa A, Barnetson RA, Cetnarskyj R,
Stark L, Porteous ME, Campbell H, Dunlop MG.
Colon Cancer Genetics Group and Academic Coloproctology, Institute of
Genetics and Molecular Medicine, University of Edinburgh and MRC Human
Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, UK.
Abstract
BACKGROUND:
Previous studies have shown that aspirin and other non-steroidal antiinflammatory drugs (NSAIDs) lower colorectal cancer (CRC) risk. However, the
lowest effective NSAID dose, treatment duration, and effects on survival are not
defined. In a large population-based case-control study, we have explored the
relationship between NSAID dose and duration, CRC risk and overall CRCspecific survival.
METHODS:
The relationship between NSAID use and CRC risk was examined in 2279
cases and 2907 controls. Subjects completed food-frequency and lifestyle
questionnaires. NSAID categories were low-dose aspirin (75 mg), non-aspirin
NSAIDs (NA-NSAIDs) and any NSAID. Users were defined as taking >4
tablets/week for >1 month. ORs were calculated by logistic regression models
and adjusted for potential confounding factors. Effect of NSAID use on all-cause
and CRC-specific mortality was estimated using Logrank tests and Cox's
hazard models.
RESULTS:
In all, 354 cases (15.5%) were taking low-dose aspirin compared to 526
controls (18.1%). Low-dose aspirin use was associated with decreased CRC
risk (OR 0.78 95% CI 0.65 to 0.92, p=0.004), evident after 1 year and
increasing with duration of use (p(trend)=0.004). NA-NSAID and any NSAID
use were also inversely associated with CRC. There was no demonstrable
effect of NSAIDS on all-cause (HR 1.11, p=0.22, 0.94-1.33) or CRC-specific
survival (HR 1.01, p=0.93, 0.83-1.23).
CONCLUSION:
This is the first study to demonstrate a protective effect against CRC associated
with the lowest dose of aspirin (75 mg per day) after only 5 years use in the
general population. NSAID use prior to CRC diagnosis does not influence
survival from the disease.
Ann Rheum Dis. 2011 May;70(5):818-22. Epub 2010 Sep 10.
The appropriate use of non-steroidal anti-inflammatory drugs in rheumatic
disease: opinions of a multidisciplinary European expert panel.
Burmester G, Lanas A, Biasucci L, Hermann M, Lohmander S, Olivieri I,
Scarpignato C, Smolen J, Hawkey C, Bajkowski A, Berenbaum F, Breedveld F,
Dieleman P, Dougados M, MacDonald T, Mola EM, Mets T, Van den Noortgate
N, Stoevelaar H.
Department of Rheumatology and Clinical Immunology, Charité - University
Medicine, Free University and Humboldt University Berlin, Charitéplatz 1 10117,
Berlin, Germany. [email protected]
Abstract
INTRODUCTION:
Given the safety issues of non-steroidal anti-inflammatory drugs (NSAID) and
the robustness of guidelines, making treatment choices in daily clinical practice
is increasingly difficult. This study aimed systematically to analyse the opinions
of a multidisciplinary European expert panel on the appropriateness of different
NSAID, with or without the use of a proton pump inhibitor (PPI), in individual
patients with chronic rheumatic disease.
METHODS:
/Using the Research and Development/University of California at Los Angeles
appropriateness method, the appropriateness of five (non-)selective NSAID with
or without a PPI was assessed for 144 hypothetical patient profiles, ie, unique
combinations of
cardiovascular
and
gastrointestinal
risk
factors.
Appropriateness statements were calculated for all indications.
RESULTS:
All options without PPI were considered appropriate in patients with no
gastrointestinal/cardiovascular risk factors. Cyclooxygenase-2 selective
inhibitors (C2SI) alone and non-selective NSAID plus PPI were preferred for
patients with elevated gastrointestinal risk and low cardiovascular risk.
Naproxen plus PPI was favoured in patients with high cardiovascular risk. For
the combination of high gastrointestinal/high cardiovascular risk the use of any
NSAID was discouraged; if needed, naproxen plus PPI or a C2SI plus PPI could
be considered.
DISCUSSION:
The panel results may support treatment considerations at the level of individual
patients, according to their gastrointestinal/cardiovascular risk profile.
Cochrane Database Syst Rev. 2011 Jan 19;(1):CD007854.
Acupuncture for primary dysmenorrhoea.
Smith CA, Zhu X, He L, Song J.
Centre for Complementary Medicine Research, The University of Western
Sydney, Locked Bag 1797, Penrith South DC, New South Wales, Australia,
2751.
Abstract
BACKGROUND:
This review examined the currently available evidence supporting the use of
acupuncture to treat primary dysmenorrhoea.
OBJECTIVES:
To determine the efficacy and safety of acupuncture in the treatment of primary
dysmenorrhoea when compared with a placebo, no treatment, or conventional
medical treatment (for example oral contraceptives and non-steroidal antiinflammatory medication (NSAIDs)).
SEARCH STRATEGY:
The following databases were searched (from inception until March 2010): the
Cochrane Menstrual Disorders and Subfertillity Group Trials Register, Cochrane
Central Register of Controlled Trials (CENTRAL) (The Cochrane Library),
PubMed, CINAHL, PsycINFO, Chinese Biomedical Literature Database (CBM),
Chinese Medical Current Content (CMCC), China National Knowledge
Infrastructure (CNKI), VIP database, Dissertation Abstracts International,
BIOSIS, AMED (The Allied and Complementary Medicine Database), Acubriefs,
and Acubase.
SELECTION CRITERIA:
Inclusion criteria included all published and unpublished randomised controlled
trials comparing acupuncture with placebo control, usual care, and
pharmacological treatment. The following modes of treatment were included:
acupuncture, electro-acupuncture, and acupressure. Participants were women
of reproductive age with primary dysmenorrhoea during the majority of the
menstrual cycles or for three consecutive menstrual cycles, and moderate to
severe symptoms.
DATA COLLECTION AND ANALYSIS:
Meta-analyses were performed using odds ratios (OR) for dichotomous
outcomes and mean differences or standard mean differences (SMD) for
continuous outcomes, with 95% confidence intervals (CI). Primary outcomes
were pain relief and improved menstrual symptoms, measured by self-rating
scales. Other outcomes included use of analgesics, quality of life, and absence
from school or work.
MAIN RESULTS:
Ten trials were included in the review with data reporting on 944 participants.
Six trials reported on acupuncture (n = 673) and four trials (n = 271) reported on
acupressure. There was an improvement in pain relief from acupuncture
compared with a placebo control (OR 9.5, 95% CI 21.17 to 51.8), NSAIDs (SMD
-0.70, 95% CI -1.08 to -0.32) and Chinese herbs (SMD -1.34, 95% CI -1.74 to 0.95). In two trials acupuncture reduced menstrual symptoms (for example
nausea, back pain) compared with medication (OR 3.25, 95% CI 1.53 to 6.86);
in one trial acupuncture reduced menstrual symptoms compared with Chinese
herbs (OR 7.0, 95% CI 2.22, 22.06); and in one trial acupuncture improved
quality of life compared with usual care.There was an improvement in pain relief
from acupressure compared with a placebo control (SMD -0.99, 95% CI -1.48 to
-0.49), and in one trial acupressure reduced menstrual symptoms compared
with a placebo control (SMD -0.58, 95% CI -1.06 to -0.10). The risk of bias was
low in 50% of trials.
AUTHORS' CONCLUSIONS:
Acupuncture may reduce period pain, however there is a need for further welldesigned randomised controlled trials.