Techniques for assessing knee joint pain in arthritis

Abstract

The assessment of pain is of critical importance for mechanistic studies as well as for the validation of drug targets. This review will focus on knee joint pain associated with arthritis. Different animal models have been developed for the study of knee joint arthritis. Behavioral tests in animal models of knee joint arthritis typically measure knee joint pain rather indirectly. In recent years, however, progress has been made in the development of tests that actually evaluate the sensitivity of the knee joint in arthritis models. They include measurements of the knee extension angle struggle threshold, hind limb withdrawal reflex threshold of knee compression force, and vocalizations in response to stimulation of the knee. A discussion of pain assessment in humans with arthritis pain conditions concludes this review.

Figure 1

Development of punctate (A) and dynamic (B) allodynia and weight bearing deficit (C) following intraarticular injection of monosodium iodoacetate (MIA, 2 mg; ■) MIA or saline (○) in the right knee. (A) Baseline (BL) paw withdrawal thresholds (PWT) were determined in both hind paws prior to injection. PWT to von Frey hair stimulation of the plantar paw surface were assessed on various days post-injection. Results are expressed as median force (g) required for a paw withdrawal in 10 animals per group (vertical bars represent first and third quartiles). * P < 0.05, ** P < 0.01, *** P < 0.001 significantly different (Mann-Whitney U test) from saline-treated group at each time point. (B) Baseline (BL) paw withdrawal latencies (PWL) to stroking the plantar paw surface with a cotton bud were determined for both hind paws prior to injection. Results are expressed as mean PWL (s) in 10 animals per group (vertical bars represent ± SEM). * P < 0.05, ** P < 0.01, *** P < 0.001 significantly different (one-way ANOVA followed by Dunnett's posthoc test) from saline-treated group. (C) Baseline (BL) hind paw weight distribution was determined prior to injection. Changes in hind paw weight distribution were assessed on various days post-injection. Results are expressed as mean change in weight distribution (contralateral-ipsilateral) (g) in 10 animals per group (vertical bars represent ± SEM). * P < 0.05, ** P < 0.01, *** P < 0.001 significantly different (one-way ANOVA followed by Dunnett's posthoc test) from saline-treated group. Reprinted from [46], Copyright 2004, with permission from Elsevier.

Figure 2

Time course of the changes of three outcome measures in rats with a kaolin/carrageenan (K/C)-induced arthritis. (A) Circumference of the knee before and after K/C injection. (B) Angle at which the knee could be extended before eliciting struggling behavior in the rat. (C) Vocalization threshold of the compression force, which was applied to the knee. Post-injection time is expressed as hours (h) or days (d) after K/C injection. Pre-injection control was taken one day before the injection (-1 d). Asterisks indicate values significantly different from the pre-injection control value by one-way ANOVA followed by the Dunnett's posthoc test (n = 10). Symbols and error bars represent mean ± SE. Reprinted from [33], Copyright 2002, with permission from Elsevier.

Figure 3

Increased audible and ultrasonic vocalizations in the K/C model of arthritic pain. (A, B) Original recordings of ultrasonic vocalizations evoked by innocuous (upper trace) and noxious (lower trace) stimulation of the knee joint in a rat before (A) and after (B) induction of arthritis with intraarticular kaolin and carrageenan injections. Mechanical stimuli were applied for 15 s; duration of the recording period was 1 min. Vocalizations during and after stimulation (VDS and VAD, respectively) were analyzed separately. (C) Duration of audible and ultrasonic VDS increased significantly 6 h after induction of arthritis compared to the values measured in the same animals before arthritis (n = 16). Stimuli of innocuous (left side) and noxious (right side) intensities evoked VDS of longer duration in arthritic animals compared to controls. (D) Duration of ultrasonic, but not audible, VAD following innocuous (left) and noxious (right) stimuli increased significantly in the arthritis pain model (6 h postinduction; n = 16). Symbols and error bars represent mean ± SE. ** P < 0.01, *** P < 0.001. Reprinted from Han JS & Neugebauer V [54]. PAIN 2005;113-211-222. Used with permission from the International Association for the Study of Pain^®.

Figure 4

Altered thresholds for mechanosensation (A) and pain (B) in patients with rheumatoid arthritis and osteoarthritis. (A) Mechanical sensation thresholds (g) for normal (Norm), rheumatoid arthritis (RA) and osteoarthritis (OA) patients, determined by von Frey monofilament testing. The RA and OA groups had significantly higher average mechanical sensation thresholds in both knees. Monofilament diameter scores for each knee were converted to grams per protocol convention for threshold determination. Average and standard error mechanical sensation scores for both knees and for the most symptomatic (worst) knee are demonstrated. * P <0.05 when compared to normal controls, analyzed by paired and unpaired Student t-tests. (B) Mechanical pain threshold scores (g) for Norm, RA and OA patients, determined by von Frey monofilament testing (see A). The average pain threshold for both knees and for the most painful (worst) knee was significantly lower in RA patients than in the Norm group. The average pain threshold for both knees and for the most painful knee in OA patients was significantly lower than in the Norm group. * P < 0.05 when compared to normal controls, analyzed by paired and unpaired Student t-tests. Reprinted from [59], Copyright 2003, with permission from Elsevier.