Delayed-Onset Muscle Soreness: Making It a Better Model for Analgesic Studies
Delayed-onset muscle soreness is an important experimental model and clinical pain state that has been used extensively to evaluate analgesic efficacy.
Delayed-onset muscle soreness (DOMS) is a common pain that all athletes are familiar with.
DOMS is different from acute pain in that this type of pain develops 12 to 24 hours after exercise and is a side effect of microscopic muscle damage repair. DOMS does not usually require treatment because it is self limited.1
There is no particular need for more medications to treat DOMS, but the condition is important for another reason.
“Delayed-onset muscle soreness is an important experimental model and clinical pain state that has been used extensively to evaluate analgesic efficacy,” said Neil Singla, MD, chief scientific officer at Lotus Clinical Research at Huntington Hospital in Pasadena, California.
Singla and colleagues recently published a pilot study in PAIN suggesting ways in which study design characteristics of the DOMS research model can be improved.
To do this, they designed a randomized, placebo-controlled, double-blind study that compared the efficacy of topical diclofenac sodium gel (DSG) to a placebo in 24 healthy volunteers with exercise-induced DOMS. 2
This topical NSAID is already approved and has been shown to be effective for treating pain of osteoarthritis. 2
“We assumed the DSG would have the ability to demonstrate analgesic efficacy in a DOMS model if appropriate study design characteristics were selected,” said Singla. 2 The purpose was to advance experimental technique, not to confirm the usefulness of the topical NSAID. 2
Advantages of Using DOMS as a Pain Model
“DOMS is a clinical pain syndrome in the world of sports medicine, and considered in that world worthy of attention. In my world of pain management, it's really a model that we hope and expect will generalize to musculoskeletal pain in general. The advantage of studying DOMS over acute musculoskeletal clinical pain is that these clinical syndromes are nightmares to study. You need hundreds or thousands of patients. It takes a huge enterprise to recruit them, and there have been many failed studies. DOMS can be studied in a single center with 20 or 30 healthy volunteers, and you can have an answer in a few months,” said Nathaniel Katz, MD, president of Analgesic Solutions and assistant professor of anesthesia at Tufts University School of Medicine in Boston. Katz wrote a commentary that accompanied the study in PAIN. 4
The advantage of a pain model like DOMS is experimental accuracy.
The study is cleaner and more sensitive. The problem is that the clean and more sensitive the study, the less likely it may be to generalize to other clinical musculoskeletal pain syndromes.
Actual clinical pain studies may be easier to generalize but not as sensitive. For example, every ankle sprain is different. That makes clinical studies much harder to control. 2
Making DOMS a Better Pain Model
“The limitations of stylized pain models (meaning you produce a naturally occurring pain syndrome, such as DOMS, in a highly standardized way) is always generalizability. If it works in DOMS, does that mean it will work in flare-ups of osteoarthritis? In low back pain? In an acute sprain? The flip side of this is ‘negative generalizability,' if you will: If it doesn't work in DOMS, does that mean it won't work in these other syndromes?” noted Katz.
A drawback of the DOMS model has been a lack of consistency in study design. The study by Singla's group notes that this can lead to both false positive and false negative results. They identify several key factors that can be used to strengthen these studies. False positive results may result from inappropriate blinding or from poorly defined endpoints. 2
In reviewing previous studies, the researchers found that many were not fully blinded. It is also critical that these investigations pre-specify a primary endpoint that will be used to evaluate the analgesic effect and the method by which that endpoint will be calculated. 2
Keys to preventing false negative results include strict baseline entry criteria, and strict control of compliance. In this pilot study, moderate to severe pain was required and subjects were not made aware of what the baseline intensity score needed to be. Subjects were housed in research units to assure protocol compliance for dosing, pain diary entries, and periods of restricted ambulation.2
Study Methods and Findings
Twenty-four healthy volunteers underwent a placebo response education program before the study. DOMS was induced through supervised, standardized, repetitive quadriceps muscle exercise. DOMS was assessed within 24 to 48 hours after exercise. Categorical and numeric pain ratings were recorded. Subjects who met the inclusion criteria were given DSG to apply to one leg and a placebo to apply to the other leg. Treatments were given every 6 hours for 48 hours. 2
Pain intensity was assessed at rest, walking, and standing after treatment over 48 hours. The primary endpoint was less pain in the treated leg while walking. Pain difference was statistically significant. Experimental assay sensitivity was good. Placebo response rate was low. The authors conclude that DOMS studies can benefit from best practices used for other analgesic research studies. 2
Significance for Clinical Pain
Clinical DOMS usually responds to ice packs, massage, or oral pain relievers. This study confirmed that topical DSG is useful for mild to moderate muscle pain, but that was not the significant part of the study. “Our model exhibited excellent assay sensitivity and was safely conducted over a short period of time. Similar investigations may validate the design features that impact the assay sensitivity of analgesic end points in DOMS models,” says Singla. 2
“Primary care providers generally don't get stuck in the weeds of study interpretation, which is a good thing, because all these studies can be challenging to interpret. The FDA does a very good job interpreting clinical trial data and writing product labels that indicate, in their reasoned view, what pain syndromes the product is appropriate to be used for, and how it should be used. That's a good starting place for practitioners,” says Katz. he work of Singla and his group may make that starting place a bit more reliable. 4
Medically reviewed by: Pat F. Bass III, MD, MS, MPH
2. Singla N, et al. Pain. 2015; 1036-1045.
4. Katz N, et al. Pain. 2015; 156:981-982.