Kay H. Steen

Chapter 8. Tissue acidosis in nociception and pain

Publisher Summary This chapter focuses on the tissue acidosis in nociception and pain. Local imbalance of perfusion and metabolism may be suggested to be the common mechanism generating tissue acidosis. Even in inflammation, the metabolic turn-over may be more enhanced, for example, by accumulation of inflammatory cells, than the local blood flow that should lead to lactic acid accumulation. Leukocytes, as well as myocytes, can actively transport lactic acid into the interstitial space. The delayed hyperalgesia observed with experimental tissue acidosis in humans seems to be reflected in a concomitantly delayed decrease of mechanical thresholds of cutaneous nociceptors, in vitro , which occurs upon repeated or prolonged exposure to low pH. A striking feature of pH-induced pain and nociceptor excitation is the synergism with mediators of inflammation encountered with tissue acidosis in inflamed areas. Preventing tissue acidosis may neither be possible nor even desirable; however, blocking pH-induced nociceptor excitation may be of great help to controlling pain of various origins.

Pain due to tissue acidosis : a mechanism for inflammatory and ischemic myalgia ?

To study the role of protons in ischemic muscle pain we employed the submaximal effort tourniquet technique" and, in a second attempt, an intramuscular pressure infusion of acid phosphate buffer. The pH measured in the forearm skin covering the muscles at work during the tourniquet test continuously dropped to a mean value of pH 7.00 +/- 0.26, starting 1 min after the contractions, while the pain increased in direct correlation with the hydrogen ion concentration (r = 0.96). After restoring the blood supply, the intradermal proton concentration decreased more slowly than the muscular pain. The same subjective quality of deep muscular pain was achieved with pressure infusion of acid phosphate buffer (pH 5.2) into the forearm muscles. Constant flow rates evoked constant, apparently non-adapting magnitudes of pain with a log-linear stimulus-response relationship (r = 0.93). Changes in flow rate were followed by changes in pain ratings with a certain phase lag. We conclude that muscular pain induced by infusion of acidic phosphate buffer and pain from ischemic contractions are generated through the same mechanisms based on the algogenic action of protons.

Sustained graded pain and hyperalgesia from harmless experimental tissue acidosis in human skin

The present study was performed to decide whether tissue acidosis can induce sustained pain and, by that, possibly contribute to the pain in inflammation or ischaemia. A motorized syringe pump was used to infuse an isotonic phosphate buffer solution (pH 5.2) via sterile filter and cannula into the palmar forearm skin of human subjects (n = 6). This resulted in a localized burning pain sensation (edema and flare response) that was sustained as long as a constant flow was maintained. Flow rates between 1.2 and 12 ml/h were needed to reach individual pain ratings around 20% of a visual analogue scale (VAS). Increasing the flow in multiples of this basic rate led to approximately log-linear increases in individual pain ratings with reasonable congruence of the slopes. Stopping the pump or cooling the skin close to the cannula caused an abrupt pain relief. Prolonged infusion at flow rates producing pain ratings around 20% VAS led to localized changes in mechanical sensitivity: The touch threshold increased--as it did with control infusion of phosphate buffer at pH 7.4. However, the punctate force producing a threshold sensation of pain dropped from 64 to 5.7 mN (median values); the final level was usually reached within 15 min. In conclusion, experimental tissue acidosis provides a controllable and harmless method to produce sustained, graded and spatially restricted pain and hyperalgesia to mechanical stimulation.

Inflammatory mediators potentiate pain induced by experimental tissue acidosis.

&NA; Electrophysiological evidence from cutaneous nociceptors suggested a synergism between excitatory actions of inflammatory mediators (IM) and low pH. In human skin it is possible to induce constant ongoing pain with continuous infusion of acid buffer. This method was used to study the interaction with mediators of inflammation psychophysiologically. A skin area on the palmar forearm of 6 subjects (either gender, age 22–35 years) was continuously infiltrated with a phosphate buffered electrolyte solution (pH 5.2) using a motorized syringe pump that was adjusted so as to produce constant pain of about 20% on a visual analog scale (VAS; extending from ‘no’ to ‘unbearable pain’). Pain was assessed on the VAS at 10‐sec intervals; the rating was called up by means of an acoustic signal. An additional cannula was placed in the skin before the infusion of acidic buffer started. Injections of an acidic combination of IM (BK, 5‐HT, HIS, PGE2) 0.2 ml were then given through the cannula at intervals of 10 min in a randomized double blind order of concentrations. The other arm was used for negative control, i.e. IM in neutral solution were injected into normal skin continuously infiltrated with a buffer solution at pH 7.4. The IM induced dose‐dependent, transient burning pain on both arms — markedly more intense and prolonged, however, in the acidotic skin (P < 0.004, U‐test). The difference corresponded to a 10‐fold increase in algogenic potency with 10−7 M IM, being smaller with 10−6 and 10−5 M concentration. The interaction between low pH and IM was mutual: additional injections of plain phosphate buffer (pH 5.2) into the acidotic skin were significantly more painful (20‐fold) after application of IM than under control conditions. Thus, we tend to conclude that it is the inflammatory mediators that potentiate the algogenic effect of low pH rather than vice versa. Tissue acidosis appears as a dominant factor in inflammatory pain.

Topical acetylsalicylic, salicylic acid and indomethacin suppress pain from experimental tissue acidosis in human skin

&NA; Topically applied acetylsalicylic acid (ASA), salicylic acid (SA) and indomethacin were tested in an experimental pain model that provides direct nociceptor excitation through cutaneous tissue acidosis. In 30 volunteers, sustained burning pain was produced in the palmar forearm through a continuous intradermal pressure infusion of a phosphate‐buffered isotonic solution (pH 5.2). In 5 different, double‐blind, randomized cross‐over studies with 6 volunteers each, the flow rate of the syringe pump was individually adjusted to result in constant pain ratings of around 20% (50% in study 4) on a visual analog scale (VAS). The painful skin area was then covered with either placebo or the drugs which had been dissolved in diethylether. In the first study on 6 volunteers, ASA (60 mg/ml) or lactose (placebo) in diethylether (10 ml) was applied, using both arms at 3‐day intervals. Both treatments resulted in sudden and profound pain relief due to the cooling effect of the evaporating ether. With lactose, however, the mean pain rating was restored close to the baseline within 6–8 min while, with ASA, it remained significantly depressed for the rest of the observation period (another 20 min). This deep analgesia was not accompanied by a loss of tactile sensation. The further studies served to show that indomethacin (4.5 mg/ml) and SA (60 mg/ml) were equally effective as ASA (each 92–96% pain reduction) and that the antinociceptive effects were due to local but not systemic actions, since ASA and SA did not reach measurable plasma levels up to 3 h after topical applications. With a higher flow rate of acid buffer producing more intense pain (VAS 50%), ASA and SA were still able to significantly reduce the ratings by 90% or 84%, respectively. On the other hand, by increasing the flow rate by a factor of 2 on average, during the period of fully developed drug effect it was possible to overcome the pain suppression, which suggests a competitive mechanism of (acetyl‐) salicylic antinociception.

The pH response of rat cutaneous nociceptors correlates with extracellular [Na+] and is increased under amiloride.

Excess hydrogen ions induce sustained nociceptor excitation as well as pain, and this has been suggested, with evidence from sensory ganglion cells, to result from gating a slowly inactivating sodium/calcium inward current. In the rat skin‐nerve preparation, isolated receptive fields of pH‐sensitive C‐fibre terminals were exposed to low‐pH solutions of various sodium concentrations. The pH responses showed a good correlation with log [Na+]e, which supports the above model. Amiloride has previously been shown to block a pH‐induced Na+ current involved in sensory transduction in hamster taste cells; however, it has been shown to act differently in cutaneous nociceptors. Amiloride induced a dose‐dependent increase in and prolongation of the nociceptive pH responses, with a prominent acceleration of the onset. The latter could be mimicked by replacing external sodium with sucrose, thus impeding sodium‐proton antiport. Together, the findings indicate functional expression of amiloride‐sensitive Na+/H+‐antiporters, which enable the nociceptive nerve endings to extrude invading H+. Intracellular acidification may thus compete with Na+/H+ exchange, and pHi may be decisive in the transduction of nociception and pain from tissue acidosis.

Dose-dependent competitive block by topical acetylsalicylic and salicylic acid of low pH-induced cutaneous pain.

&NA; In a human acid pain model, which uses continuous intradermal pressure infusion of a phosphate‐buffered solution (pH 5.2) to induce localized non‐adapting pain, the flow was adjusted to result in constant pain ratings of about 20% or 50% on a visual analog scale (VAS). Six volunteers in each group participated in 4 different placebo‐controlled double‐blind cross‐over studies to measure rapidly evolving cutaneous analgesia from topically applied new ointment formulations of acetylsalicylic acid (ASA) and salicylic acid (SA) as well as of commercial ibuprofen and benzocain creams. Similar, log‐linear dose‐response curves were found for both ASA and SA, significant in effect at 3 g/ kg and higher drug contents and reaching saturation level at 15 or 30 g/ kg, respectively, which, 20 min after application, caused a mean pain suppression of 95% using ASA and 80% using SA. Half‐maximal effects were achieved using 3 g/kg ASA or 15 g/kg SA. The SA action was also clearly slower to develop. With an increased flow of the acidic buffer, producing lower effective tissue pH and more intense pain, the effect of ASA and SA decreased to 73% pain suppression. A competitive mechanism of both drug effects was suggested by the fact that, with 15 g/kg ASA and SA, pain reduction could be reversed by increasing the buffer flow by a factor of 1.75., on average. Commercial ibuprofen (50 g/kg) and benzocain creams (100 g/kg) were comparably as effective as ASA and SA, but the local anesthetic caused a loss of all cutaneous sensations while the touch threshold (von Frey) under the specific analgesics was the same as under the placebo ointment. Thus, topical applications of non‐steroidal anti‐inflammatory drugs (NSAIDs) dissolved in different ointment formulations have proven dose‐dependently effective and specific in suppressing experimental acidotic pain by a local and competitive mechanism.

Plasma levels after peroral and topical ibuprofen and effects upon low pH-induced cutaneous and muscle pain

Cutaneous applications are gaining popularity in the treatment of cutaneous pain and of painful disorders in joints and muscle. The low pH‐pain model in human skin has previously been able to demonstrate the effects of NSAIDs in dose‐dependent manner and to establish time‐effect relationships. We examined the analgesic action of ibuprofen after cutaneous application and compared the effects with oral administration. The two studies (with n = 12 subjects each) were performed in a double‐blind, randomized fashion with a 1‐week cross‐over interval. In study 1 volunteers received intradermal infusions with phosphate buffered saline solution of pH 5.2 and received either 800 mg ibuprofen per os and topical placebo, or 4 g of a 5% commercial ibuprofen gel topically applied and oral placebo capsules, respectively. In study 2 the same protocol was applied with painful intramuscular infusion of stronger, isotonic phosphate buffer (pH 5.2). The flow rate of the pH‐infusion was individually adjusted to induce pain with a magnitude of 20% on a visual analogue scale (ranging from ‘no’ (0%) to ‘unbearable pain’ (100%)). Ibuprofen (S‐, R‐) plasma levels after oral administrations were measured with HPLC, and after topical applications, by gas chromatography combined with mass spectroscopy to determine plasma levels in the range of ng/ml. In the cutaneous model pain ratings decreased to zero after topical verum gel within 45 min of the observation period of 55 min. Pain reduction after peroral ibuprofen was of the same magnitude, but was achieved within only 30 min. In the muscle model, the commercial ibuprofen gel did not reduce the pain in the acidic muscle. The peroral ibuprofen was less effective in the muscle compared to the skin pain model, although there was a significant progressive pain reduction within 55 min. Reasons for the differential susceptibility of cutaneous vs muscular acidosis pain to ibuprofen remain to be established.

Unilateral linear lichen planus with mucous membrane involvement.

Linear lichen planus is a rare distinctive variant of lichen planus (LP) characterized by a pruritic eruption of lichenoid, violaceous papules in a linear distribution that sometimes assume a Blaschko line pattern. We describe a 33-year-old woman who presented with a 4-month history of a slightly pruritic unilateral linear array of papular lesions on the left side of her neck that were clinically and histologically consistent with linear LP. Two months after the onset of her skin disease she developed typical lesions with a lacy white pattern on the left lateral aspect of her tongue and the left buccal mucosa with a striking predominance for the left side. Clinically the lesions on the patients neck were similar to lichen striatus or lichenoid epidermal naevus, a variant of linear verrucous epidermal naevus. However, the histological features and the fact that later in the course of her disease the patient developed typical LP of the oral mucosa suggest that this patient has the rare condition of linear LP with unilateral restriction.

Analgesic profile of peroral and topical ketoprofen upon low pH-induced muscle pain

&NA; Topical analgesics are widely marketed for treatment of muscle and joint pain. We have recently developed a model of muscle pain and have used this model to evaluate the efficacy of commercially available topical and peroral ketoprofen in order to evaluate the time‐ and dose‐dependence of analgesia. In the present study, we examined the dose‐ (0, 50, and 100 mg) and time‐dependence (hourly to 8 h) of commercially available peroral and topical ketoprofen. In order to achieve infusion times of 8 h (and thus study the time course of analgesic action), we adapted the model of low pH‐induced muscle pain in humans to these requirements by applying the infusions continuously for 10 min every hour for 8 h. We found that the 10 min infusion produced reliable and consistent pain levels that were reproducible over the 8 h of the study. The study was performed double‐blind, randomized, and with a 1‐week interval between each of five different sessions (cross‐over). Altogether six volunteers underwent intramuscular infusions of isotonic phosphate‐buffered saline solution of pH 5.2; during each 8 h session the infusion was switched on eight times with a duration of 10 min at 50 min intervals (there was no infusion during the 50 min interval). The intramuscular infusion of low pH phosphate buffer induced a localized dull‐aching or stinging muscle pain sensation; the flow rate of the pH infusion was individually adjusted to induce pain of a magnitude of 20% on a visual analogue scale (ranging from ‘no pain’ (0%) to ‘unbearable pain’ (100%)). Twenty minutes after starting the infusion the volunteers received a capsule with either a placebo or 50 or 100 mg ketoprofen perorally and, in addition, either placebo gel or 50 or 100 mg of a 2.5% commercial ketoprofen gel was applied topically to the skin. One of the sessions included a placebo gel and an oral placebo. The intensity of the recurrent pain stimulus was significantly reduced by 59% following administration of 100 mg peroral ketoprofen within the first 3 h (P<0.03, Wilcoxon test); this analgesia lasted up to the sixth hour of the experimental protocol. Oral ketoprofen (50 mg) was less effective and reduced the pain intensity by 45% (P<0.05) from only the second to the third hour. In contrast, pain reduction after topical ketoprofen application was not of the same magnitude but appeared to be faster to develop (with a maximum effect within 1 h) on average. The maximum pain suppression with 100 mg topical 2.5% ketoprofen gel was by 51% (significant with P<0.03), while 50 mg topical ketoprofen produced a non‐significant reduction of 29%. The apparent analgesia was rapid to develop but transient and pain ratings increased back to baseline values within 3 h for the 100 mg dose and within 2 h for the 50 mg dose. This data suggests that topical application of commercial gel‐based systems does not provide long‐lasting analgesia in the muscle when compared to perorally‐dosed ketoprofen. In addition, the data show that even doses of 100 mg peroral ketoprofen do not provide complete relief of muscle pain.