No Added Pain-Relief Benefit With Use of the Psychotropic Drug Duloxetine (CYMBALTA, DRIZALMA SPRINKLE) in Osteoarthritis Patients, Study Shows

Osteoarthritis is the most common joint disorder in the U.S.; it leads to chronic pain and disability, especially among older adults.[1] It is characterized by progressive inflammation and pathological changes in the joint tissue, including bone and cartilage.[2]

The nonsurgical management of knee and hip osteoarthritis includes pain relief through nonpharmacological and pharmacological treatment approaches.[3] Nonpharmacological approaches include exercise and physiotherapy as well as weight loss, if applicable. Pharmacological approaches include analgesics, mainly acetaminophen (TYLENOL) and nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen (ADVIL, MIDOL LIQUID GELS, MOTRIN IB, TAB-PROFEN) and naproxen (ALEVE, ANAPROX DS, EC-NAPROSYN, NAPRELAN, NAPROSYN). However, the long-term use of the latter medications is associated with adverse effects. For example, NSAIDs can cause gastrointestinal ulcers and bleeding, kidney damage and increased risk of heart attacks or strokes.

In 2010, the Food and Drug Administration approved the oral drug duloxetine (CYMBALTA, DRIZALMA SPRINKLE) — a selective serotonin and norepinephrine reuptake inhibitor — for the treatment of chronic musculoskeletal pain (including pain due to osteoarthritis) in adults.[4],[5] This approval was based on two 13-week randomized, placebo-controlled clinical trials in knee osteoarthritis subjects who were treated in specialty clinics.[6],[7] Previously, the agency had approved duloxetine for the treatment of major depression, generalized anxiety disorder, pain due to diabetic peripheral neuropathy, and fibromyalgia.

In contrast, citing insufficient evidence that duloxetine’s benefits outweigh its risks, the European Medicines Agency (EMA) rejected the drug as a treatment for somatic pain (including pain due to osteoarthritis).[8],[9]

In agreement with the EMA, Public Citizen’s Health Research Group has designated duloxetine as a Do Not Use drug for treating any type of musculoskeletal pain in adults. We also have designated the drug as Do Not Use for all other approved indications because it offers no benefit over other available treatment options but is associated with risks of well-known serious adverse effects — including low sodium levels in the blood, potentially fatal liver injury, fainting, falls and severe skin reactions — that are higher than those of alternative medications.[10],[11],[12]

In support of our position against the use of duloxetine in osteoarthritis patients, a new study fails to show any benefit for adding the drug to usual care in primary care settings among hip or knee osteoarthritis patients with chronic pain. This study was funded by the Dutch government and published in the May 2022 issue of Arthritis and Rheumatology.

The new study[13]

The study was a “pragmatic” randomized clinical trial that recruited its subjects from offices of primary care doctors in the Netherlands. The subjects were adults with documented hip or knee osteoarthritis who reported related joint pain on most days of the last three months but did not show a sufficient response to acetaminophen and NSAIDs and had previous NSAIDs-related adverse effects or contraindications to use of these drugs. They also had no contraindication for using duloxetine and were not current users of antidepressants or neuropathic-pain medications.

Overall, 132 subjects were enrolled in the trial: 66 were randomized to receive a once-daily dose of duloxetine (in addition to usual care), and 66 were randomized to receive usual care alone. Usual care consisted of education, dietary and other lifestyle recommendations, physiotherapy and analgesics, with intra-articular (inside the joints) steroid injection also permitted, if needed. The study was open-label; subjects and their doctors as well as the on-site research team were not blinded to the random assignment of duloxetine treatment. Only the researchers were blinded to that information.

There were no clinically relevant nor statistically significant differences in pain scores (measured using a questionnaire called the Western Ontario and McMaster Universities Osteoarthritis Index) between subjects in both groups after three and 12 months of follow-up. Likewise, there were no beneficial effects for duloxetine among the 47% of subjects who had symptoms of centrally sensitized pain — likely resulting from repeated or prolonged harmful stimuli (such as injury) being detected by certain receptors in the body — which was assessed using another standardized questionnaire for assessing pain.

More subjects in the duloxetine group were referred to orthopedic surgeons, resulting in total knee or hip replacements in five subjects, compared with none in the usual-care group after 12 months of follow-up. In contrast, nine subjects in the usual-care group received intra-articular steroid injections, compared with three subjects in the duloxetine group.

Per the study protocol, duloxetine was gradually discontinued after three months of use in subjects randomized to take the drug who experienced no pain improvement or had intolerable adverse effects related to the drug. As a result, 65% of subjects in the duloxetine group discontinued the drug (mostly after three months of use) due to adverse effects (49%), lack of benefit (24%) or both (18%). Constipation, excessive sweating, nausea, weight loss and yawning were significantly more commonly reported by subjects in the duloxetine group.

The researchers highlighted certain strengths of their study. First, it enrolled older osteoarthritis subjects who had related symptoms for several years and had more other medical conditions than those in previous studies. Second, it only enrolled subjects who had inadequate responses to first-line pharmacologic treatment, which was not often done in previous clinical trials. Third, the study followed subjects for a year, substantially longer than other trials. However, the researchers noted that further study of duloxetine is needed in patients with centralized pain (using quantitative sensory testing) to be able to rule out any potential benefits for the drug in these patients with the same certainty as they did for the overall study subjects.

In conclusion, until future studies show a clear benefit with the use of duloxetine in osteoarthritis patients, including those with centralized pain, we cannot recommend using it for these patients.

What You Can Do

If you have osteoarthritis, try to lose weight if needed, and start by relying on an individualized long-term program of physical therapy, exercise or tai chi because studies show that these treatments can be effective.[14],[15],[16],[17]

Do not take duloxetine to relieve osteoarthritis-related pain. If you are currently taking this drug, do not stop it suddenly without consulting your doctor in order to avoid its withdrawal symptoms.[18]

Avoid opioid analgesics because of their limited effectiveness for osteoarthritis and their substantial adverse effects, including addiction, respiratory depression and somnolence.[19] Per the May 2022 issue of Worst Pills, Best Pills News, we caution against the use of intra-articular steroid injections into the hips, especially high-dose ones, because they are potentially associated with high risk of rapidly destructive hip disease.[20]

Report all serious adverse events related to the use of duloxetine or other drugs to the FDA’s MedWatch adverse-event reporting program by visiting http://www.fda.gov/MedWatch or by calling 800-FDA-1088.
 

References

[1] Zhang Y, Jordan JM. Epidemiology of osteoarthritis. Clin Geriatr Med. 2010;26(3):355-369.

[2] Katz JN, Arant KR, Loese RF. Diagnosis and treatment of hip and knee osteoarthritis: A review. JAMA. 2021;325(6):568–578.

[3] Ibid.

[4] Eli Lilly and Company. Label: duloxetine (CYMBALTA). July 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/021427s056lbl.pdf. Accessed August 3, 2022.

[5] Eli Lilly and Company. News release: FDA approves Cymbalta for the management of chronic musculoskeletal pain. November 4, 2010. https://investor.lilly.com/static-files/c5a45faf-219c-4899-ad6b-d453c918ad8e. Accessed August 3, 2022.

[6] Chappell AS, Desaiah D, Liu-Seifert H, et al. A double-blind, randomized, placebo-controlled study of the efficacy and safety of duloxetine for the treatment of chronic pain due to osteoarthritis of the knee. Pain Pract. 2011;11(1):33-41.

[7] Chappell AS, Ossanna MJ, Liu-Seifert H, et al. Duloxetine, a centrally acting analgesic, in the treatment of patients with osteoarthritis knee pain: a 13-week, randomized, placebo-controlled trial. Pain. 2009;146(3):253-260.

[8] European Medicines Agency. Human medicine European public assessment reports - product information: duloxetine (CYMBALTA). December 21, 2021. https://www.ema.europa.eu/documents/product-information/cymbalta-epar-product-information_en.pdf. Accessed August 3, 2022.

[9] European Medicines Agency. Questions and answers: Refusal of a change to the marketing authorisation for Ariclaim, Cymbalta and Xeristar (duloxetine). July 21, 2010. https://www.ema.europa.eu/documents/smop/questions-answers-refusal-change-marketing-authorisation-ariclaim-cymbalta-xeristar_en.pdf. Accessed August 3, 2022.

[10] Eli Lilly and Company. Label: duloxetine (CYMBALTA). July 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/021427s056lbl.pdf. Accessed August3, 2022.

[11] Do not use: Duloxetine (CYMBALTA). June 2012. Worst Pills, Best Pills News. https://www.worstpills.org/newsletters/view/795. Accessed August 3, 2022.

[12] Duloxetine. Also avoid its use in recurrent depression. Prescrire Int. 2010;19(111):280.

[13] van den Driest JJ, Schiphof D, Koffeman AR, et al. No added value of duloxetine in patients with chronic pain due to hip or knee osteoarthritis: A cluster-randomized trial. Arthritis Rheumatol. 2022;74(5):818-828.

[14] Katz JN, Arant KR, Loeser RF. Diagnosis and treatment of hip and knee osteoarthritis. A review. JAMA. 2021;325(6):568-578.

[15] Gay C, Chabaud A, Guilley E, Coudeyre E. Educating patients about the benefits of physical activity and exercise for their hip and knee osteoarthritis. Systematic literature review. Ann Phys Rehabil Med. 2016;59(3):174-183.

[16] Nguyen C, Lefèvre-Colau MM, Poiraudeau S, Rannou F. Rehabilitation (exercise and strength training) and osteoarthritis: A critical narrative review. Ann Phys Rehabil Med. 2016;59(3):190-195.

[17] Svege I, Nordsletten L, Fernandes L, Risberg MA. Exercise therapy may postpone total hip replacement surgery in patients with hip osteoarthritis: A long-term follow-up of a randomised trial. Ann Rheum Dis. 2015;74(1):164-169.

[18] Eli Lilly and Company. Label: duloxetine (CYMBALTA). September 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/021427s056lbl.pdf. Accessed August 3, 2022.

[19] Katz JN, Arant KR, Loeser RF. Diagnosis and treatment of hip and knee osteoarthritis. A review. JAMA. 2021;325(6):568-578.

[20] Study links hip steroid injections to rapidly destructive hip disease. Worst Pills, Best Pills News. May 2022. https://www.worstpills.org/newsletters/view/1465. Accessed August 3, 2022.