Acidic buffer induced muscle pain evokes referred pain and mechanical hyperalgesia in humans

Abstract

While tissue acidosis causes local deep-tissue pain, its effect on referred pain and mechanical muscle hyperalgesia is unknown. The aim of this study was to investigate a human experimental acidic muscle pain model using a randomized, controlled, single-blinded study design. Seventy-two subjects (36 female) participated in three visits, each involving one 15 min intramuscular infusion into the anterior tibialis muscle: acidic phosphate buffer (pH 5.2) at 40 ml/h (N=69) or 20 ml/h (N=54), normal phosphate buffer (pH 7.3) at 40 ml/h (N=70), or isotonic saline at 40 ml/h (N=19). Pain ratings and pressure sensitivity of superficial and deep tissues were assessed before, during, and 20 min after infusion. Acidic buffer produced light to moderate, rate-dependent, muscle pain (not sex-dependent) compared to the control infusions, that referred pain to the ankle in 80% of women and 40% of men. Pain did not vary across self-reported menstrual phases. Pressure pain thresholds (PPTs) were reduced over the infused muscle with acidic infusion, defined as primary mechanical hyperalgesia. PPTs decreased at the ankle in those with referred pain in response to acidic buffer, i.e. referred mechanical hyperalgesia, but not at the foot. No pain or changes in PPTs occurred in the contralateral leg. These results demonstrate muscle acidosis can lead to local and referred pain and hyperalgesia, with significant sex differences in development of referred pain.

Figures

Figure 1

Mean pain ratings (Borg CR10 scale) across all subjects at: A) the local infusion site (anterior tibialis muscle) and B) the referred pain site (ankle) including baseline (- 4 min), catheter insertion (-2 min), infusion period (0 – 15 min), and recovery (15 – 35 min) for each infusion: acidic phosphate buffer, pH 5.2, 40 ml/hr (Acidic 40; N=69); acidic phosphate buffer, pH 5.2, 20 ml/hr (Acidic 20, N=52); normal phosphate buffer, pH 7.3, 40 ml/hr (PB control, N=71); and 0.9% saline, 40 ml/hr (saline control, N=19).

Figure 2

Representative examples from eight individuals (4F:4M) of pain drawings of local and referred pain during each 15 min infusion: acidic phosphate buffer, pH 5.2, 40 ml/hr (acidic 40); acidic phosphate buffer, pH 5.2, 20 ml/hr (acidic 20); normal phosphate buffer, pH 7.3, 40 ml/hr (PB control); and 0.9% saline, 40 ml/hr (saline).

Figure 3

Mean (SEM) pain-time integral (area under the pain-time curve) for A) all subjects by infusion for the anterior tibialis muscle (local site) and ankle (referred site) during the 15 minute intramuscular infusion; B) females only and C) males only. Infusions include: acidic phosphate buffer, pH 5.2, 40 ml/hr (acidic 40); acidic phosphate buffer, pH 5.2, 20 ml/hr (acidic 20); normal phosphate buffer, pH 7.3, 40 ml/hr (PB control); and 0.9% saline, 40 ml/hr (saline). * indicates significant (p

Figure 4

Associations (r, Spearman’s rho) and regression lines between peak referred pain and peak local pain for each infusion: acidic phosphate buffer, pH 5.2, 40 ml/hr (acidic 40, black circle); acidic phosphate buffer, pH 5.2, 20 ml/hr (acidic 20, gray square); normal phosphate buffer, pH 7.3, 40 ml/hr (PB control, gray triangle); and 0.9% saline, 40 ml/hr (saline control, white circle). Referred pain was moderately correlated to local pain across all but the saline infusion.

Figure 5

Mechanical pressure pain thresholds (PPTs) relative to baseline pre-infusion values at A) mean of upper and lower anterior tibialis muscle sites, B) ipsilateral ankle (referred pain site), C) ipsilateral 1st and 2nd metatarsal web space, D) contralateral lower anterior tibialis muscle, and E) contralateral ankle; with F) sensory test locations indicated as x = ipsilateral and □ = contralateral test sites. Negative values indicate mechanical hyperalgesia. * Significantly less than control infusions (p ≤ 0.05). † Significantly greater than acidic 40 infusion (p ≤ 0.05).

Figure 6

Mean (SEM) percent change in PPTs relative to baseline, comparing those with referred pain (≥ 0.5 ankle pain, black) to those without (white) during each infusion: A) acidic phosphate buffer, pH 5.2, 40 ml/hr (acidic 40); B) acidic phosphate buffer, pH 5.2, 20 ml/hr (acidic 20); C) normal phosphate buffer, pH 7.3, 40 ml/hr (PB control); and D) 0.9% saline, 40 ml/hr (saline). The six test sites were collapsed to four for illustrative purposes: Anterior Tibialis (upper and lower anterior tibialis); ankle (referred site); web space (between 1st and 2nd metatarsals); and contralateral (ankle and lower anterior tibialis locations). * Significant between group differences (p ≤ 0.05); negative values indicate mechanical hyperalgesia.