Noting that drug-induced arthralgia can occur as a side effect of a large number of common medications, this author offers insights on how to recognize and manage drug-induced joint pain.
The most recent data from a sample population survey of civilian households reveals that 47.2 percent of the population takes at least one prescription drug a month while 20.8 percent of the population takes three or more prescription medications a month.1
The musculoskeletal system can be a target organ for adverse drug effects. Medications for the treatment of arthritis, psychosis and epileptic disorders can profoundly affect the musculoskeletal system.2 These drug-induced musculoskeletal disorders represent a broad clinical spectrum, ranging from asymptomatic biological abnormalities to severe life-threatening disorders, in which either arthralgia and/or myalgia are the only presenting patient complaints.3
By understanding the biologic mechanisms of these drugs and their ability to induce rheumatological adverse effects, the clinician may be better able to prescribe medications while minimizing or even preventing adverse effects. Having a heightened awareness of the drug-induced arthralgia will also enable podiatrists to diagnose side effects caused by medications commonly prescribed by other physicians.
The epidemiology of most musculoskeletal adverse reactions has been documented mainly through case reports or spontaneous pharmacovigilance data.2 Uncertainty does exist as to whether a particular drug has caused an adverse reaction in the context specific to the musculoskeletal system. It is important to recognize when a patient’s rheumatic complaints are due to drugs. However, this awareness is difficult because of the large number of drugs that have been implicated and the diversity of clinical presentation.
Therefore, a need does exist to explore the medical literature for valid evidence proving that specific medications do indeed cause drug-induced disorders within the field of rheumatology. Hart presents data describing drug-induced rheumatic disorders that are categorized in one of nine main groups.4 These groups are as folllows:
• drug-induced precipitation or aggravation of a preexisting or larval rheumatic disease;
• precipitation of a transient drug-induced syndrome in people who were previously arthritis-free;
• electrolyte and fluid disturbances causing arthritis or arthralgia;
• drug side effects causing joint symptoms;
• serum sickness and similar drug reactions;
• bone lesions due to drugs;
• drug-induced myopathy syndromes;
• pseudoscleroderma; and;
• irritation from intra-articular injections.
Arthralgia is joint pain. It is a symptom, not a disease. Acute joint pain is any arthralgia that one expects to resolve within six weeks to six months.5 One may use the symptom as a diagnosis until determining the true cause of the joint pain or indefinitely if examination and testing are inconclusive. The underlying cause of arthralgia may be articular or non-articular in origin, affecting either just one or multiple joints. The exact incidence is not known because, as a symptom, arthralgia accompanies a broad range of disparate conditions.
Research has demonstrated the chondrotoxicity of fluoroquinolones experimentally and all quinolones appear to be chondrotoxic.2 Experimentation has shown that statins, another class of medications, cause myalgia, joint damage and joint pain. A number of other medications that are in widespread use are suspected of causing arthralgia complaints.2
Accordingly, let us take a closer look at pharmacovigilance data within the context of frequently prescribed medications that result in drug-induced rheumatic disorders, specifically arthralgia.
Understanding Pharmacovigilance And Medical Causation
It was not until the disaster caused by thalidomide in 1961 that the first systematic international effort began to address drug safety. The principal goal of pharmacovigilance is the detection of adverse events related to the use of drugs that are unknown or novel in terms of clinical pattern, severity or frequency.2 The World Health Organization defines pharmacovigilance as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or other drug-related problems.6
Pharmacovigilance continues to play a crucial role in meeting the challenges posed by the ever increasing range and potency of medicines, all of which carry an inevitable and sometimes unpredictable potential for harm.
The definition of an adverse effect is an untoward physical sign or symptom, an abnormal assessment, or cluster of signs or symptoms. The impact of adverse drug effects results in significant cost and inflicts unnecessary harm (sometimes fatal harm) to patients.7 Adverse effects would function as a distraction because the presence of an adverse effect could mimic actual biological pathology and thus distract the clinician from identifying the actual cause of the patient’s presenting symptoms. (For example, if a medication adverse effect was nausea and vomiting and physicians did not identify the nausea and vomiting as a adverse effect, they may perform an radiological test and blood work on the patient, thus being distracted from the actual cause of the nausea and vomiting. This can result in unnecessary investigations and a delay in treatment.6,8
The difficulty with the diagnosis of adverse drug reactions is that these reactions represent exceedingly complex clinical phenomena.9 This complexity may be related to: discrepancies in the incidence of adverse drug reactions reported in epidemiological studies; the non-specificity and suggestibility of symptoms attributed to adverse drug reactions; and inter-observer disagreement among experts in the diagnosis of adverse drug reactions.9
The definition of medical causation is an adverse effect that occurs as a result of treatment with medication, biological, vaccine, device or procedure.10 We can describe causation in “degrees of relatedness” as unrelated or definitely, probably or possibly related to a treatment.10,11 Hill’s criteria for causation outlines a systemic approach for using scientific judgment to infer causation from statistical associations observed in epidemiologic data.12
What You Should Know About The Effects Of Common Medications
I conducted a search of various electronic sources for data regarding drug-induced arthralgia as a medication adverse effect during the time period of 1953 to 2011. The medications I selected for review were the 200 most frequently prescribed (brand and generic names) in 2010 as measured by the IMS Institute for Healthcare Informatics.13 The data were primarily qualitative and were based on reports in the current compendium of recent journal articles and package inserts.2-4,14,15
The prevalence rates of arthralgia as an adverse drug effect were not available for all 200 medications reviewed. Current literature sources resolved conflicting information presented in reference materials. The recommendations presented in the table, “A Guide To Medications, Arthralgia Prevalence Rates And Mechanism Descriptions,” center on the applied sciences of pharmacology and physiology, as well as clinical intuitive judgment that balances patient benefit with patient risk.
As part of my search of databases and literature, I derived counts and rates arithmetically to determine the frequency of possible mechanisms or explanations for medication-induced arthralgia using the nine main groups Hart previously described.4
During this review, I noted duplicates were present, owing to the listing of medications by both brand name and generic name. Therefore, the actual number of different medications in the review was 117. Reported arthralgia adverse effects occurred with 78 out of 117 drugs reviewed (66.7 percent). This research revealed that 14 medications have prevalence rates of 5 percent or greater for drug-induced arthralgia. These medications and prevalence rates for drug-induced arthralgia are as follows:
• Risedronate (Actonel®, Warner Chilcott) 11.5 to 32.8 percent
• Fluticasone (Flovent®, GlaxoSmithKline) 1 to 19 percent
• Conjugated estrogen (Premarin®, Pfizer) 7 to 14 percent
• Rosuvastatin (Crestor®, AstraZeneca) 10.1 percent
• Venlafaxine (Effexor XR®, Pfizer) 1 to 10 percent
• Clopidogrel bisulfate (Plavix®, Bristol-Myers Squibb/Sanofi Aventis) 2.5 to 6.3 percent
• Clonidine (6 percent)
• Pregabalin (Lyrica®, Pfizer) 3 to 6 percent
• Carvedilol (1 to 6 percent)
• Meloxicam (0.5 to 5.3 percent)
• Atorvastatin calcium (Lipitor®, Pfizer) 5.1 percent
• Olanzapine (Zyprexa®, Eli Lilly) 5 percent
• Tramadol (1 to 5 percent)
• Lovastatin (0.5 to 5 percent)
The number of reviewed medications with a noted arthralgia prevalence rate between 1 to 4.9 percent accounted for 30 (38.4 percent). The reviewed medications with a reported arthralgia prevalence rate of less than 1 percent accounted for seven (8.9 percent) reviewed medications. Twenty-seven (34.6 percent) of the 117 drugs reviewed had a narrative notation that researchers had reported arthralgia without any numerical prevalence rate. Thirty-nine medications of the 117 review drugs (33.3 percent) did not have any description of drug-induced arthralgia as an adverse effect.
In my review, the most frequent explanation or mechanism for drug-induced arthralgia cited in the medical literature for 50 (64.1 percent) of the reviewed medications was “drug side effects causing joint symptoms in previously disease-free patients.” This was followed by “drug-induced electrolyte and fluid disturbances causing arthritis or arthralgia in nine (11.5 percent) of the reviewed medications while the explanations of “damage to joint” and “either serum sickness or the presence of antinuclear antibodies” were reasons for drug-induced arthralgia for seven (8.9 percent) of the reviewed medications. Drug-induced lupus erythematosus (DILE) was a possible explanation for three (3.8 percent) of the reviewed medications. Finally, osteonecrosis was a possible explanation for two (2.6 percent) of the 78 reviewed medications.
Keys To Diagnosing Adverse Effects Due To Drug-Induced Arthralgia
Although this article is based on subjective data, these adverse effects are common and can affect the patient’s quality of life. Moreover, the effect that prescription medications have on a patient’s overall health is profound. Drug-induced rheumatic disorders represent a broad clinical spectrum from asymptomatic biological abnormalities to severe and even life-threatening diseases, even though arthralgia is the only presenting clinical feature in many cases.3
For example, previous studies have identified certain classes of medications that may contribute to the patient’s perception of arthralgia.2-4,14,15 Studies have well documented the precipitation of a transient arthralgia in previously arthritis-free patients.2-4
Be aware that “drug side effects causing joint symptoms in previously disease-free patients” may need early recognition to avoid carrying out unnecessary clinical tests, which may delay treatment and contribute to higher medical costs. Both the clinical presentation and severity of drug-induced arthralgia may vary from one patient to another for the same drug, depending on the dose employed, the duration of therapy, the pathophysiological status of the patient and/or genetic and environmental factors. The clinician should remember that drug-induced arthralgias often resolve on withdrawal of the offending pharmacologic agent.
Electrolyte and fluid disturbance may cause discomfort in the region of joints. Hart reports that fluid loading rarely causes more than mild discomfort. Researchers have reported this with the use of corticosteroids, estrogens and oral contraceptives.4 Muscle cramping and/or arthralgia may be due to sodium depletion from excessive use of diuretics. Finally, diuretics may precipitate an acute attack of gout that the patient may interpret as arthralgia.
Drug-induced lupus erythematosus is a lupus-like syndrome temporally related to continuous drug exposure that resolves after discontinuation of the offending drug. It tends to affect older patients (ages 50 to 70), men more than women and Caucasians more than African-Americans. Hoffman first described this in 1945 as a side effect of sulfadiazine.14,15 Drug-induced systemic lupus erythematosus has at least two of the following criteria: recovery within one year upon withdrawal of the drug; absence of features suggestive of idiopathic systematic lupus erythematosus; or absence of antibodies before taking the drug. Pharmacological agents causing drug-induced systemic lupus erythematosus fall into two groups: those with definite evidence of association and those with unproven association and isolated cases.
Serum sickness is an immune complex–mediated hypersensitivity reaction characterized by fever, rash, arthritis, arthralgia and other systemic symptoms. Serum sickness–like reaction is clinically similar to the classic or primary form, and is attributed to many non-protein drugs, including beta-lactam antibiotics, ciprofloxacin (Cipro), sulfonamides, bupropion (Wellbutrin, Valeant Pharmaceutiucals), streptokinase, metronidazole, allopurinol, carbamazepine and others. The primary therapy in patients with serum sickness is discontinuation of the offending agent. Therefore, the identification of the offending agent is of the utmost importance.
Groups of patients treated with the following beta-blockers (practolol, acebutolol (Sectral), labetalol, atenolol, timolol, metoprolol, pindolol and oxprenolol) all displayed increased development of antinuclear antibodies relative to patients on other medication. These drugs may be weak inducers of iatrogenic lupus in comparison with major drugs like procainamide, high doses of hydralazine (Apresoline) and D-penicillamine. Careful monitoring of rheumatic conditions is essential when prescribing drugs with the potential for autoimmune toxicity.
A noted limitation of this report is that it was not possible to distinguish between the effects of the medications and those of underlying medical conditions and diseases being treated. The reported adverse effects may be due to either the drug or the disease.
The accompanying table, “A Guide To Medications, Arthralgia Prevalence Rates And Mechanism Descriptions,” should help address the need for a ready reference for healthcare professionals in monitoring and counseling patients regarding the potential for arthralgia side effects of their medications. The goal of this article was to raise awareness of medically significant drug-induced arthralgia and help clinicians recognize, manage and/or prevent these side effects. Most arthralgia symptoms improve after withdrawal of the drug but if withdrawal is impossible, preventative therapy is necessary.
Dr. Smith is a Clinical Assistant Professor of Podiatric Medicine and Surgery at Western University of Health Science/College of Podiatric Medicine.
1. National Center for Health Statistics. Health, United States, 2010 with Special Feature on Death and Dying. National Center for Health Statistics. Hyattsville, MD, 2011. www.cdc.gov/nchs/data/hus/hus10.pdf . Accessed March 29, 2012.
2. Conforti A, Chimaulera C, Moretti U, Colcera S, et al. Musculoskeletal adverse drug reactions: a review of literature and data from ADR spontaneous reporting databases. Curr Drug Saf. 2007;2(1):47-63.
3. Bannwarth B. Drug-induced musculoskeletal disorders. Drug Saf. 2007; 30(1):27-46.
4. Hart FD. Drug-induced arthritis and arthralgia. Drugs. 1984; 28(4):347-54
5. Palmer T, Toombs JD. Managing joint pain in primary care. J Am Board Fam Pract. 2004; 17(Suppl):S32-S42.
6. World Health Organization (WHO). The importance of pharmacovilgilance- safety monitoring of medicinal products Geneva: WHO, 2002. http://apps.who.int/medicinedocs/en/d/Js4893e/6.html . Accessed May 14, 2011.
7. Classen DC, Pestotnik SL, Evans RS, et al. Adverse drug events in hospitalized patients. Excess length of stay, extra costs, and attributable mortality. JAMA. 1997; 277(4):301-6.
8. Pirmohamed M, Breckenridge AM, Kitteringham NR, et al. Adverse drug reactions. Br Med J. 1998; 316(7140):1295-98.
9. Kramer MS. Difficulties in assessing the adverse effects of drugs. Br J Clin Pharmac. 1981; 11(Suppl1):105S-10S.
10. Marks DH. Evaluation of Medical Causation In: O’Donnell JT, ed. Drug Injury: liability, analysis and prevention, 2nd Edition. Lawyers & Judges Publishing, Tucson, 2005: 143-149.
11. Hutchinson TA, Lane DA. Assessing methods for causality assessment. J Clin Epidemiol. 1989; 42(1):5-16.
12. Hill AB. The environment and disease: association or causation? Proc R Soc Med. 1965; 58: 293-300.
13. IMS Institute for Healthcare Informatics. IMS institute reports U.S. spending on medicines grew 2.3 percent in 2010, to $307.4 billion. Press release. IMS Institute for Healthcare Informatics Web Site. http://bit.ly/hNjs5r . Published April 19, 2011. Accessed April 23, 2011.
14. McEvoy GK. AHFS Drug Information 2009. American Society of Health-System Pharmacists. Bethesda, MD, 2009.
15. Williams AL. Facts and Comparisons 2012, Wolters Kluwer Health, St Louis, 2012.