Failure to Demonstrate Any HypoalgesicEffect of Low Intensity Laser Irradiation

(830nm) of Erb’s Point UponExperimental Ischaemic Pain in Humans

Andrea S. Lowe, PhD,2 Brona C. McDowell, PhD,1 Deirdre M. Walsh, PhD,2

G. David Baxter, PhD,2* and James M. Allen, PhD1

1Rehabilitation Sciences Research Group, School of Biomedical Sciences, University ofUlster, Jordanstown BT37 0QB, Northern Ireland, U.K.

2Rehabilitation Sciences Research Group, School of Health Sciences, University ofUlster, Jordanstown BT37 0QB, Northern Ireland, U.K.

Background and Objective: This study assessed the putative an-algesic effect of low intensity, near-infrared laser irradiation(830nm; 1.5 & 9.0J/cm2; continuous wave).Study Design/Materials and Methods: The current study wascompleted under double-blind conditions using a standardisedform of the submaximal effort tourniquet technique. Healthy na-ive female volunteers (n = 48) attended on two occasions for paininduction in the non-dominant upper limb, the first during whichbaseline data were obtained and on a second occasion duringwhich subjects were randomly allocated to either control, pla-cebo, or one of two treatment groups. In the treatment groups,irradiation was applied to ten points on the ipsilateral Erb’s pointimmediately prior to the pain induction procedure at the param-eters stated: For the placebo condition, sham ‘‘irradiation’’ wasdelivered by applying the laser unit without activating the probe.Pain was measured using computerised visual analogue scalesand McGill Pain Questionnaires to assess ‘‘current pain inten-sity’’ and ‘‘worst pain experienced,’’ respectively.Results: Whereas analysis of variance and appropriate posthoctests showed a trend toward hypoalgesia at a radiant exposure of1.5J/cm2, no significant effects of laser therapy were found.Conclusions: These results do not provide convincing evidencefor the clinical potential of low intensity laser irradiation as apain relieving modality, at least at the parameters used. Furtherwork is thus necessary to provide objective quantifiable data onthe putative clinical efficacy of this modality and the relevance (ifany) of irradiation parameters. Lasers Surg Med 20:69–76, 1997

© 1997 Wiley-Liss, Inc.

Key words: analgesia; experimental pain; laser therapy; biostimulation

INTRODUCTION

While the use of laser devices at relativelylow intensities (<30J/cm2) has recently capturedthe imagination of clinicians and the medico-sci-entific community as a potentially effective mo-dality for the treatment of wounds and soft tissueinjuries [1–3], the use of this therapy for the reliefof pain has also attracted considerable scepticismfrom some sources [4–6]. The principal reasons

for such scepticism are the generally poor qualityof the research published within this field, thelack of any obvious mechanism of action, and therange of laser treatment parameters cited by au-

*Correspondence to: G.D. Baxter, University of Ulster, Jor-danstown BT37 0QB, Northern Ireland, U.K.

Accepted for publication 18 June 1996.

Lasers in Surgery and Medicine 20:69–76 (1997)

© 1997 Wiley-Liss, Inc.

thors. The continued preponderance of foreignlanguage publications further confounds reviewof the literature on this application; consequently,the putative efficacy of laser therapy for the reliefof pain remains debatable [2,4–7].

In spite of such controversy, results of sev-eral surveys of current clinical practice in lasertherapy carried out at this centre have indicatedthe popularity and apparent efficacy of this mo-dality for the treatment of pain of various aeti-ologies [8, 9]. As a consequence, in an effort toestablish the positive impressions of survey re-spondents, we have previously completed severalinvestigations of the hypoalgesic potential of thistherapy upon experimental ischaemic pain undercontrolled laboratory conditions using the pulsedmultisource/multiwavelength diode array cited asthe most popular treatment unit in the surveys[7, 10–12]. In demonstrating a weak but signifi-cant treatment-mediated hypoalgesic effect withsuch therapy, the findings of these ischaemic painstudies corroborated the generally positive re-sults reported in the literature from previous ex-perimental work in animals [13–15] and in hu-mans [16, 17].

Parallel studies at this centre have employedantidromic in vivo nerve conduction studies inhumans to determine the effects of low intensitylaser radiation upon peripheral neurophysiologyand skin temperature. In contrast to the experi-mental pain studies already outlined, these neu-rophysiological investigations have relied uponthe use of a single continuous wave 830nm infra-red laser diode applied at relatively low radiantexposures (ø9.0J/cm2), rather than the higherdosage (31.9J/cm2) multiwavelength irradiationused in the former at a variety of pulse repeti-tion rates. These nerve conduction studies haveconsistently demonstrated laser-mediated effectsthat are critically dependent upon irradiation pa-rameters [7, 18–21], and in particular, that thegreatest increases in conduction latency (corre-sponding to decreases in conduction velocity) oc-cur at a radiant exposure of 1.5J/cm2 [20]. Al-though these results are interesting, their preciserelevance to the putative hypoalgesic effects ofthese devices is unclear; thus the neurophysiolog-ical substrate(s) of laser-mediated pain relief re-main occult. Nevertheless, if this neurophysiolog-ical effect does form any part of the substrates forthe hypoalgesic effects claimed for these devices,one might expect good correlation between mea-sured latency changes and hypoalgesic efficacy.Given the importance of establishing a scientific

basis for the continued clinical application of thismodality for the relief of pain, or indeed recom-mendation of cessation of its use in this applica-tion, investigation of the hypoalgesic effects of ir-radiation applied at the parameters used in thenerve conduction studies was considered to be in-dicated.

Thus the current investigation was under-taken to establish the analgesic efficacy of lowintensity continuous wave laser irradiation usinga single 830nm infrared laser diode probe uponthe standardised variation of the submaximumeffort tourniquet technique that had previouslybeen used at this centre to investigate the effectsof a multisource/multidiode array [7, 10–12]. Toallow direct comparison with the earlier neuro-physiological studies, laser was applied at two ra-diant exposures (1.5 and 9.0J/cm2), representingthe extremes of dosages used in these previousstudies [e.g., 20].

MATERIALS AND METHODSRecruitment Procedure

Ethical approval was obtained from the eth-ical committee of the University of Ulster for thecurrent study for which female subjects, who hadnot previously participated in similar experi-ments and were unfamiliar with laser therapy,were recruited from staff and students of the uni-versity. For potential subjects, mutually conve-nient times were agreed for the two attendancesnecessary (see below). During first attendance,subjects received a comprehensive briefing on therelevant experimental procedures. All were ex-pressly reminded of their right to terminate theproceedings at any point without necessarily giv-ing a reason for doing so and their attentiondrawn to the limited dangers associated with theischaemic pain induction technique. Each subjectwas then invited to ask any relevant questionsand to sign a simple consent form. In keepingwith the principles of informed consent, subjectswere informed that low intensity laser therapymight be applied during their second attendance.

Screening Procedure

Subjects’ nondominant arms, which wereused in this experiment for the purposes of paininduction, were routinely examined prior to com-mencement of the ischaemic procedure at each at-tendance. It was further determined that subjectswere currently healthy and free from any symp-toms or illnesses that would contraindicate the

70 Lowe et al.

pain induction procedure. Subjects were specifi-cally screened for peripheral neuropathy or vas-cular abnormality, hyper- or hypotension, as wellas current drug usage or current menstruation. Onthe basis of this screening procedure, it was foundnecessary to exclude five subjects from the exper-iment; a total of 53 subjects were recruited, ofwhom 48 were eventually used in the experiment.

Pain Induction Procedure

Subjects were seated at a table in a con-trolled laboratory environment, with a microcom-puter (520 ST, Atari, London, UK) used for thepurposes of pain assessment mounted on the tabledirectly in front of the subjects’ chair. Once com-fortably seated, subjects’ nondominant arms wereexposed to above the bulk of biceps/triceps androutinely examined as outlined above. When thiswas satisfactorily completed, operation of thecomputer’s mouse control to rate pain (see below)was demonstrated.

An elastic bandage was then applied to theexposed hand and forearm under constant ten-sion, up to a point ∼ 8 cm above the elbow joint,and a sphygmomanometer cuff wrapped aroundthe upper part of the limb over the bulk of biceps/triceps. With these in place, a dynamometer(Martin vigorometer) fitted with a medium-sizeballoon was used to assess maximal grip strength(MGS) in the arm. Thus assessed, a marker on thedynamometer was set to read 75% of this maxi-mal value and subjects were asked to elevate thearm vertically above the head for a 60-second pe-riod in order to desanguinate the limb under thecombined action of gravity and the elastic ban-dage. With the arm still vertical, the cuff was in-flated rapidly (<2s) to a pressure of 250 mmHg.The point at which tourniquet inflation was com-pleted was recorded as time zero, a timer started,and the first of 12 computerised Visual AnalogueScales (VAS) for subjects to rate current pain in-tensity (see below) at 1-minute intervals was pre-sented. Once pain had been rated in this way, thearm was returned to a resting position on the ta-ble and, using the previously set dynamometer,subjects performed 20 hand grip exercises withinthe next minute, holding each grip for a period of1 second. At the end of this second minute, a sec-ond VAS was presented for subjects to rate theircurrent level of pain. It should be stressed that,although returning the arm to a resting positionusually decreased the pressure in the tourniquetcuff, a constant pressure of at least 200 mmHgwas maintained throughout the procedure.

Deflation

After the tenth VAS was presented, the tour-niquet cuff was slowly deflated over a 2-minuteperiod to allow subjects’ forearms to resanguinategradually. A further two VAS were presentedduring this period at 1-minute intervals as before.On conclusion of each experiment, the tourniquetcuff and elastic bandage were removed and sub-jects’ forearms routinely examined to identify anyobvious trauma, undesired side effects, or resid-ual pain. No such problems were evident in thesubjects used in this study.

Pain Measurement

Computerised VAS were used to assess cur-rent pain intensity at 1-minute intervals for thetotal duration of the procedure, including the de-flation period (i.e., 12 minutes) as already out-lined. At each minute point, a VAS was presentedfor a total of 15 seconds, with the marker on theVAS located halfway along the analogue scale foreach new presentation of the scale, the positionand orientation of which were randomised by theapplication program. Subjects used the integralclick switch on the mouse to finalise and recordthe reading once they were happy that the posi-tion of the marker along the scale adequately re-flected the current level of pain experienced. EachVAS reading was recorded by the program as apercentage of the total length of the analoguescale and automatically stored to disk for subse-quent analysis.

In addition to this continuous rating of painthroughout the procedure, subjects were also in-terviewed using a single standard McGill PainQuestionnaire (MPQ) at the end of each atten-dance. The MPQ was selected to provide an addi-tional measure of the quantitative and qualita-tive aspects of the worst pain experienced duringthe procedure; five pain scores were calculatedfrom the completed MPQ: Sensory (S), Affective(A), Evaluative (E), Miscellaneous (M) scores, aswell as an overall Pain Rating Index (PRI) score.

Second Attendance

After exactly 48 hours, subjects were re-quired to attend a second pain induction sessionduring which they were randomly assigned to oneof four experimental groups: (1) control condition(neither active nor sham irradiation), (2) placebocondition, using the specified laser in contact withthe subjects’ skin but without activating the laserprobe; (3) treatment condition 1, in which subjects

Hypoalgesic Effect Failure 71

received a radiant exposure of 1.5J/cm2 using an830 nm GaAlAs continuous wave laser probe, and(4) treatment condition 2, in which subjects re-ceived a radiant exposure of 9.0J/cm2 using thesame laser.

For the purposes of this investigation, dou-ble-blind conditions applied with one investigatorindependently applying the treatment accordingto a predesigned master schedule and the second(who was ignorant of the other aspects of the ex-periment) inducing and recording pain to limitthe potential for experimenter bias. Results weresubsequently analysed independently.

Irradiation Parameters

Laser irradiation was administered immedi-ately before pain induction commenced on the sec-ond attendance. Such irradiation was deliveredusing a GaAlAs 830 nm laser diode (CBM Master3, CB Medico, Vaeloese, Denmark) applied per-pendicularly in contact with the skin over the ip-silateral Erb’s point. This point was identified atthe junction of the midclavicle and the sternoclei-domastoid muscle and was chosen to allow irradi-ation over the underlying brachial plexus, wherethe nerve trunks supplying the upper limb aremost superficial. For the purposes of laser appli-cation, the skin overlying Erb’s point was ex-posed, marked with a standardised array of 10equally spaced points, and each point irradiatedin quick succession for either 5 or 30 seconds perpoint to deliver the required dosages. The physi-cal parameters of the laser unit used here weremeasured as: wavelength: 830 nm; average poweroutput: 30 mW; area of spot size: 0.1 cm2 irradi-ance: 300 mW/cm2. Calibration of the laser wascompleted at the beginning of each experiment.

Using the equation:

Time (s) =Radiant Exposure (J/cm2)

Irradiance (W/cm2)

irradiation times to deliver radiant exposures of1.5 and 9.0J/cm2 were calculated to be 5 and 30seconds per point, respectively, as already indi-cated.

Analysis

All data were analysed using analysis ofvariance (ANOVA) to determine whether ob-served changes between groups were statisticallysignificant (P<0.05).

RESULTS

Visual Analogue Scale Scores

Results for subjects’ first attendance aresummarised in Figure 1, which plots VAS scores(%) for all groups against time (minutes); pointsshow means ± s.e.m. for each group, which arelabelled based upon subsequent (second atten-dance) group allocation. This graph clearly illus-trates the progressive increase in pain intensityexperienced by subjects during the first 10 min-utes of this ischaemic pain induction procedure,followed by the rapid decrease in reported painintensity during cuff deflation (Fig. 1).

Analysis of these data using repeated mea-sures ANOVA showed no significant differencesbetween groups, thus indicating subjects to bewell matched for the procedure. To assess theeffect of treatments compared to control, VASscores were standardised for each subject by sub-tracting the values obtained during initial atten-dance from those obtained during second (i.e., fi-nal) attendance. Figure 2 plots such standardisedVAS difference scores (mean ± s.e.m.) againsttime (minutes); with scores standardised in thisway, hypoalgesia is represented by positive andhyperalgesia by negative values. Although no ob-vious trend was apparent from the results in thecontrol group for the majority of the experimentalprocedure, a marked hyperalgesic effect was ob-served in this group during the deflation period(i.e., at the 11th and 12th minute). In contrast, inthe placebo group a mild hypoalgesic effect wasevident up until the 6-minute point and again af-ter the 10-minute point. However, during themost painful period of the procedure (i.e., 7–10minutes), there was apparently a hyperalgesic ornocicebo effect of such sham irradiation. Of thetwo laser treatment groups, the 1.5J/cm2 groupshowed some hypoalgesic effect after the 5-min-ute point, which became more marked by the 11thand 12th minutes of the procedure. However, re-sults in the 9.0J/cm2 laser treatment group wereless clear cut. Although this group demonstratedsome hypoalgesic effects until the 6th minute, thefinal minute of the procedure found a marked in-crease in pain in this group.

Standardised ‘‘difference’’ scores were com-pared between experimental groups using re-peated measures and one factor ANOVA. Where-as the latter found some marginal differencesbetween groups at the 12-minute point, repeatedmeasures ANOVA failed to demonstrate differ-ences between groups to be significant.

72 Lowe et al.

MPQ ScoresFigure 3 plots MPQ results, standardised as

difference scores as for VAS, for the five compo-nents of the questionnaire; as for previous figures,points represent means ± s.e.m. for each groupwith hypoalgesia represented by positive and hy-peralgesia by negative scores. This figure shows

some consistent trends throughtout all compo-nents of the MPQ. Most notably, for the 1.5J/cm2

laser group results demonstrated hypoalgesic ef-fects in all but the Evaluative component of theMPQ. In contrast, results in the 9.0J/cm2 lasergroup demonstrated an hyperalgesic effect withthis level of irradiation, again in all but the Eval-

Fig. 1. Summary of Visual Analogue Scale (VAS) scores for initial attendance; (points show means ± s.e.m.).

Fig. 2. Summary of differences in initial and final Visual Analogue Scale (VAS) scores; (points show means ± s.e.m.).

Hypoalgesic Effect Failure 73

uative component of the MPQ. Perhaps most su-prisingly, results for the placebo group also showa marked hyperalgesic (i.e., nocicebo) effect withsham irradiation. In the MPQ scores for the con-trol group, no such consistent pattern was seen.MPQ data were analysed as standardised differ-ence scores using one factor ANOVA, whichshowed statistically significant differences be-tween experimental conditions for the Evaluativecomponent of the MPQ (P40.0213); no such sig-nificant differences were seen for any of the othercomponents of the MPQ. Corrected Fisher testscompleted on the evaluative score data indicatedthere to be significant differences between the1.5J/cm2 laser treatment and control groups, the9.0J/cm2 laser treatment and placebo groups, aswell as the control and placebo groups.

DISCUSSION

The putative hypoalgesic effects of low inten-sity laser irradiation remain controversial, main-ly due to the poor quality of some of the publica-tions within this field and the lack of an obviousmechanism of action [2, 4–7]. In the light of this,and on the basis of previous positive findings atthis centre, the purpose of the current study wasto investigate hypoalgesic effects of low intensityinfrared laser irradiation applied at Erb’s pointupon experimental ischaemic pain in humans. As

indicated ahbove, the standardised form of theSETT used here had already been successfullyemployed in the investigation of the hypoalgesiceffects of combined phototherapy/low intensity la-ser therapy [7, 10–12] and thus seemed to repre-sent a useful model of pain for the current study.In addition, nerve conduction studies at this cen-tre have consistently demonstrated a laser-medi-ated effect upon conduction latency and that suchobserved effects are critically dependent upon ir-radiation parameters, and in particular radiantexposure, with 1.5J/cm2 apparently representingthe most effective dosage for slowing of conduc-tion velocity [20]. If such peripheral neurophysi-ological effects upon nerve conduction latenciesrepresent a substrate for the putative hypoalgesiceffects of these devices, it might be expected thatconcomitant hypoalgesic effects would be seen atthis dosage. Thus the current study used 1.5J/cm2

as the radiant exposure for one of the laser treat-ment groups and a higher level of 9.0J/cm2 for asecond laser treatment group for comparison.

Analysis of the current results has providedlittle convincing evidence of the hypoalgesic ef-fects of low intensity laser irradiation upon exper-imental ischemic pain at the parameters usedhere. However, data for the 1.5J/cm2 laser groupdemonstrated some general trends toward hypoal-gesia, most notably for the Evaluative aspects ofthe MPQ, in which results achieved significance.

Fig. 3. Summary of differences in initial and final Pain Rat-ing Index (PRI), Sensory (S), Affective (A), Evaluative (E),and Miscellaneous (M) scores from McGill Pain Question-naires (MPQ); (columns show means ± s.e.m.). * represents

significance between placebo and 9.0J/cm2. n represents sig-nificance between control and 1.5J/cm2. [ represents signif-icance between control and placebo.

74 Lowe et al.

An interesting (although nonsignificant) no-cicebo effect was also observed with sham irradi-ation, most notably in the MPQ data. Althoughdifficult to explain, this may be due to increasedanxiety in these naive subjects who (perhaps) be-came apprehensive when the laser probe wasapplied, or due to the fact that a second experi-menter was present to deliver the laser treat-ment.

In both laser groups it is interesting to notethat even though neither group reached signifi-cance in the overall PRI scores from the MPQ, the1.5J/cm2 laser group showed a mild hypoalgesiceffect, whereas 9.0J/cm2 showed a hyperalgesic ef-fect (with the sole exception of E scores in bothcases). This inverse relationship between effectand radiant exposure is in keeping with our pre-vious findings at this centre, in isolated frog sci-atic nerve preparations in vitro [21] and anti-dromic nerve conduction studies in the humanmedian nerve in vivo [20]. Whereas in both thesenerve conduction studies, the lowest radiant ex-posures used produced the greatest effects, thelatter study in particular demonstrated that 1.5J/cm2 produced the largest (and significant) laser-mediated increase in conduction latency, corre-sponding to a decrease in conduction velocity.However, given the current findings, this slowingof nerve conduction velocity probably does notrepresent a possible substrate of the mild hypoal-gesic effects demonstrated here at the same radi-ant exposure.

Finally, although it might be suggested thatischaemic pan induction techniques may not rep-resent the best method of assessment of the painrelieving effects of laser therapy, such techniqueshave been widely used and accepted as one of thebest models of clinical pain for the laboratory as-sessment of putative pharmacological analgesics[22–26]. Furthermore, the standardised variant ofthe ischaemic technique described here also hasbeen previously used to investigate the analgesicpotential of other physical modalities, e.g., so-called H-wave therapy, a biphasic exponentiallydecaying electro-stimulation waveform, whichhas recently been promoted as an effective modal-ity for the relief of pain [27], as well as conven-tional transcutaneous electrical nerve stimula-tion (TENS) [28]. However, the most convincingevidence for the suitability of the technique forthe current study comes from our previous workon combined phototheraphy/low intensity lasertherapy; in these studies, such combined treat-ment applied to Erb’s point at relatively higher

radiant exposures (>30J/cm2) has consistentlydemonstrated a weak but significant hypoalgesiceffect [7, 10–12].

Results of the current investigation thusserve to underline the necessity of additional lab-oratory-based work to establish definitively orotherwise the analgesic potential of this modalityas a necessary precursor to any possible futureclinical trials. However, the current results can inno way be seen as a definitive base upon which toinitiate clinical studies. In addition, although notessential to determination of the efficacy of thismodality, the putative mechanism of analgesicaction of low intensity laser irradiation remainsunclear and thus contributes to the scepticismsurrounding this area. Thus the precise neuro-physiological and hypoalgesic effects of this mo-dality will only become apparent with furthercontrolled studies.

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