Pain, 24 (1986) 323-329

Elsevier

323

PA1 00858

Influence of Naloxone on Relief of Acute &o-Facial Pain by Transcutaneous Electrical Nerve

Stimulation (TENS) or Vibration

P. Hansson *, A. Ekblom *, M. Thomsson ** and B. Fjellner *** * Department of Physiology II, Karolinska Institutet, S-104 01 Stockholm, ** Department of Oral Surgery,

Siidersjukhuset, S-IO0 64 Stockholm, and *** Department of Dermatoiop, Karolinska Sjukhuset, S-l 04 Of Stockholm (Swede@

(Received 17 June 1985, revised received 14 August 1985, accepted 23 August 1985)

Summary

Twenty-eight patients suffering acute pain following operative removal of im- pacted third molars took part in the present study. In 20 patients who reported pain reduction exceeding 25% of the initial pain intensity during vibratory stimulation (100 Hz) or TENS (2 or 100 Hz), only 1 patient (given 2 Hz TENS) reported pain increase after injection of 0.8 mg naloxone (i.v.). In 8 patients, not treated with afferent stimulation, 2 experienced increase in pain intensity after naloxone injec- tion. The results show that pain relief using TENS or vibration is not influenced by naloxone.

Transcutaneous electrical nerve stimulation (TENS) (211 and, to some extent, vibratory stimulation [18] are presently in use for pain relief. The mechanisms of action for pain relief by these modes of afferent stimulation are largely unknown. Experimental evidence [8,12,20,27] has been produced, indicating that activity set up in large myelinated fibres by afferent stimulation might interact with pain transmit- ting pathways. Furthermore, the contribution of an opioid-dependent mechanism to obtain pain relief by TENS [28] and acupuncture stimulation [3,19,25] has been proposed. In these studies naloxone, an opioid antagonist, has been used as a tool to study the involvement of opioid systems in pain relief induced by afferent stimula- tion. Studying chronic pain patients, Sjolund and collaborators [6,28,29] have

0304-3959/86/%03.50 0 1986 Elsevier Science Publishers B.V. (Biomedical’ Division)

reported evidence supporting an opioid link in pain relief obtained using low frequency (train stimulation) TENS.

In the present investigation we have further studied the effect of naloxone on pain relief induced by TENS and vibratory stimulation in opiate-naive subjects with postoperative oro-facial pain. The effect of naloxone on clinical pain perception was

also studied.

Methods

Subjects

Twenty-eight patients, aged 18-39 years (16 females and 12 males), were from a clinic for oral surgery and had suffered postoperative pain (subjective pain intensity not varying more than + 10% during the last 2 h) for 3-24 h (1 patient for 6 days).

All patients had an impacted third molar surgically removed by one of the authors (M.T.), and in none of the patients were the gingival incisions made in front of the first premolar to avoid interference with cross-innervation from the contralateral

side of the mouth. Local anaesthesia, i.e., 3.5 ml Xylocain@ (20 mg/ml) containing

Adrenaline (12.5 pg/ml) (Astra Lakemedel AB) was given before surgery. No premeditation was used and none of the patients had experienced oro-facial pain for at least 2 weeks prior to surgery. No analgesics were allowed before the trials. The patients were told that they might experience pain relief, no change, or aggravation of pain during stimulation. They were also informed that two substances, commonly

used in the clinic, were to be administered to further investigate their reaction to stimulation. No hints were given concerning their normal indications. Every effort

was made to avoid suggestion. All patients were assured that they could stop the stimulation and withdraw from the trial at any time. All subjects were tested

between 13.00 and 17.00 h.

Puin assessment

Before the start of stimulation the patients were asked to rate their pain intensity by using a 5-graded verbal scale - light, light-moderate, moderate, moderate-severe

or severe pain. Patients with different pain ratings prior to stimulation were about

evenly distributed on basis of this scale. The subjects also rated their pain intensity before and after the stimulation period using a visual analogue scale (VAS), and continuously during the trial using a device with a graphic rating scale (GRS) consisting of a lever attached to a potentiometer in contact with an ink-writer, which was out of sight of the patient. For further technical description see Ottoson et al. [22] and Hansson and Ekblom [9]. The results obtained with the two scales used (VAS. continuous GRS) were consistent. The results were evaluated from the recordings with the GRS.

Administration of saline and naloxone Before start of the experiment all patients were provided with an intravenous line,

on the dorsal or ventral side of the forearm, which was coupled to a catheter. The

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catheter was used to avoid direct manipulation of the patient during the injections,

thereby minimizing indications that an injection was to be made. Furthermore, all injections of saline and naloxone (naloxone hydrochloride, Nalonee @, Endo Labora-

tories) were performed behind a screen in a double-blind hidden fashion. Only the experiment controller knew the nature of the injected substance, i.e., neither the

physician in charge of the intravenous procedure (author B.F.) nor the assistant nurse knew what substance was going to be injected. Furthermore, only the nurse was permanently present in the room during the trials. The patients were told to

indicate verbally if they felt any injection during the trial.

Afferent stimulation technique Transcutaneous electrical nerve stimulation (TENS). TENS of low and high

frequency were used. The high frequency TENS consisted of pulses of 0.2 msec duration repeated at a rate of lOO/sec. The low frequency TENS consisted of pulses

of 0.2 msec duration delivered in 71 Hz trains for 84 msec at a rate of 2 Hz. In all TENS procedures conducting carbon rubber electrodes, measuring 3.5

cm x 5 cm, were applied to the skin overlying the painful area. Using 2 Hz TENS

the intensity was adjusted so that non-painful muscular contractions were induced.

TENS at 100 Hz produced a tingling non-painful sensation. Vibratory stimulation. 100 Hz of vibratory stimulation with an amplitude of

400-800 pm was used. The probe (disc-shaped probe measuring 3 cm in diameter) was connected to an electromechanical vibrator (Briiel and Kjaer 4809) driven by a sine wave generator (Bruel and Kjaer 1047). The vibrator probe, fixed to a stand,

was applied to the skin overlying the painful area with a non-painful pressure trying to exert pressure on the underlying bone [22]. The vibratory movement amplitude was measured by a piezo-electric accelerometer (Brtiel and Kjaer 4367) attached to the stimulus probe.

All stimulation periods lasted for 45 min. Recording of the subjective pain intensity was continued for 15 min after termination of stimulation.

Experimental design Patients not receiving afferent stimulation. Eight patients rated their subjective pain

intensity continuously for 90 min using a graphic rating scale (see above). Fifteen

minutes after start of pain assessment 4 ml of saline was injected intravenously. Twenty-five minutes after saline injection 4 ml of naloxone (0.2 mg/ml) was injected. Pain assessment was thereafter continued for another 50 min.

Patients receiving afferent stimulation. Out of 32 patients assigned for treatment using TENS or vibratory stimulation 20 patients who reported pain relief of more than 25% of the initial pain intensity were given naloxone. Six patients received 100 Hz TENS, 7 patients received 2 Hz TENS and 7 patients received 100 Hz of vibratory stimulation. When the patients reported at least 25% pain relief during afferent stimulation (after 15 min + 5 min of stimulation), 4 ml of saline was injected. At about 30 min after start of stimulation 4 ml of naloxone (0.2 mg/ml) was injected. The saline injected was merely given in order to find out if a placebo response would be given, if the patient by chance noted the injection. If so, this

would give a hint to what extent confidence could be attributed to the possible effect of naloxone injection if this was felt by the patient. A change in pain intensity of less than 10%. of the length of the GRS from zero to one end of the scale, was

considered as a non-significant change in pain intensity.

Results

A finding from the present study was that in spite of warming (to 37°C) of the solutions prior to injection, 9 of the patients felt the injection of saline and/or naloxone as a sensation of coldness or, using naloxone, a smarting sensation radiating in the arm and hand. This was associated with a change in subjective pain

intensity in only two patients. One patient, receiving saline, reported a significant

increase in pain intensity about 3 min after the injection and one patient. receiving

naloxone, reported increased pain relief during vibratory stimulation.

Patients not receiving afferent stimulation

Six of the 8 subjects reported no change in pain intensity after injection of 0.8 mg of naloxone. Two patients, however, experienced a significant increase in pain intensity 2-5 min after naloxone injection.

Patients receiving afferent stimulation

Only one patient, receiving 2 Hz TENS, experienced a complete inhibition of pain reduction (within 2 min) after the injection of naloxone, i.e., an increase in pain intensity to the pretreatment level. Interestingly, this was the patient who had suffered pain for 6 days prior to treatment. Furthermore, one patient receiving 100 Hz vibration and who noted the naloxone injection reported a significant increase in pain relief within 5 min after naloxone injection. This was also seen within 2 min in

one patient receiving 100 Hz TENS. Saline did not influence the subjective pain

intensity in any of the patients.

Discussion

Patients not receiving afferent stimulation

In the present study 2 out of 8 patients reported an hyperalgesic effect of naloxone. This is comparable with earlier results in chronic pain patients by Hosobuchi et al. [lo] using 0.2-l mg of naloxone. Lindblom and Tegner [15] could not demonstrate any effect of 0.8 mg naloxone on the subjective pain intensity in chronic pain patients. Levine et al. [13] reported that naloxone in doses of 9 mg enhanced acute clinical pain. A double-blind crossover technique with intravenous injections in full view of the patients was used in their study. The contradictory results of the present study could perhaps partly be explained by the fact that we used only 0.8 mg of naloxone. However, naloxone in doses of 0.8 mg is used clinically to treat opiate intoxications and 0.4 mg of naloxone has been proved to

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antagonize analgesia produced by brain stimulation [2]. The use of a hidden

injection design in our study might also partly explain the difference of the present results from the findings by Levine et al. [13].

Furthermore, the finding that naloxone in the majority of the patients in the present study did not enhance the clinical pain is an important fact when interpret- ing the effect of naloxone on analgesia obtained using afferent stimulation.

Patients receiving afferent stimulation Somewhat contradictory results exist on the naloxone reversability of pain relief

obtained by afferent stimulation. Acupuncture analgesia has been reported to be antagonized by naloxone in animal experiments [3,25] but in man equivocal results

have been reported [5,19]. Low frequency (2.5 Hz, train stimulation) [24] and high frequency [23] TENS have been shown to increase the tooth pain threshold, an effect

not inhibited by naloxone. However, Chapman and Benedetti [4] reported naloxone

reversible effects using 2 Hz TENS studying experimental dental pain.

Clinically, failure of naloxone to reverse analgesia obtained using high frequency TENS has been reported by several authors [e.g., 1,7,28,30]. Salar et al. [26] found an increased concentration of opioid-like substances in the cerebrospinal fluid (CSF) in

a group of patients without pain, who were given high frequency TENS. Eriksson and Sjolund [6] have reported that the induction time for maximal relief of pain is

significantly longer for low frequency than for high frequency TENS. Also, Sjolund and Eriksson [28] demonstrated that analgesia induced by low frequency (train stimulation) TENS, in chronic pain patients, was in the majority antagonized by naloxone. Furthermore, Sjolund et al. [29] have shown that low frequency TENS, applied to the area of pain, was associated with an increased concentration of opioid-like substances in the lumbar CSF in patients suffering pain in the thoracic

and lumbar regions. This could not be demonstrated in patients reporting relief from

trigeminal neuralgia. The authors suggested a segmental mechanism for opioid-link- ed analgesia using low frequency TENS.

The finding from the present study that naloxone did not antagonize analgesia in 19 out of 20 patients supports a non-naloxone reversible mechanism in pain relief obtained with the used modes of afferent stimulation. The finding that naloxone did not affect the vibration induced pain relief agrees with earlier findings by Lundeberg [17] in patients suffering chronic epicondylitis pain.

Some precautions have to be taken when interpreting the results of studies using

naloxone trying to antagonize analgesia. It has been shown [11,16] that naloxone predominantly exerts its antagonistic effects at p-receptors. The extent of interaction

of naloxone with presently known and unknown opioids at other receptors related to analgesic mechanisms is obscure. Also, if opioids are involved in pain relief by TENS or vibration the possibility exists that naloxone in the dose used only prevented further pain relief during stimulation. Furthermore, Levine et al. [14]

found an analgesic effect of naloxone in low doses (0.4 and 2 mg) but hyperalgesia from higher doses (7.5 and 10 mg). An analgetic effect of naloxone seems unlikely since none of the 8 patients receiving naloxone without concomitant afferent stimulation reported pain decrease. Therefore, the pain decrease after administration

of naloxone seen in 2 patients receiving afferent stimulation may rather reflect further pain reduction due to the effect of afferent stimulation.

In conclusion. the results of the present study indicate that pain relief by the used

modes of vibration or TENS is not mediated by opioid mechanisms which naloxone in doses of 0.8 mg counteracts.

Acknowledgements

The authors are greatly indebted to Mrs. Carin Carlstedt and MS Ulla Lindgren

for secretarial help, to MS Siv Bjorklund, R.N., Mrs. Ulla Hansson, R.N., and MS Anette Norman, R.N.. for assistance, and to Profs. Jan Lannergren and Ake Flock

for comments on the manuscript. The study was supported by grants from Karolinska Institutets Fonder and was

approved of by the ethical committee of Karolinska Institutet.

References

1 Abram& S.E.. Reynold, A.C. and Cusick, J.F., Failure of naloxone to reverse analgesia from

transcutaneous electrical stimulation in patients with chronic pain, Anesth. Analg., 60 (1981) 81-84.

2 Adams. J.E., Naloxone reversal of analgesia produced by brain stimulation in the human. Pain, 2 (1976) 161-166.

3 Akil. H., Mayer. D.J. and Liebeskind, J.C.. Antagonism of stimulation-produced analgesia by

naloxone. a narcotic antagonist. Science, 191 (1976) 961-962.

4 Chapman. CR. and Benedetti, C.. Analgesia following transcutaneous electrical stimulation and its

partial reversal by a narcotic antagonist, Life Sci.. 11 (1977) 1645-1648.

5 Chapman, C.R.. Colpitts. Y.M.. Benedetti, C.. Kitaett, R. and Gehrig, J.D.. Evoked potential

assessment of acupunctural analgesia: attempted reversal with naloxone, Pain, 9 (1980) 183-197.

6 Eriksson. M. and Sjolund. B., Acupuncture-like electroanalgesia in TNS-resistant chronic pain. In: Y.

Zotterman (Ed.), Sensory Functions of the Skin, Pergamon Press, Oxford, 1975, pp. 575-581.

7 Freeman, T.B., Campbell, J.N. and Long, D.M., Naloxone does not affect pain relief induced by

electrical stimulation in man, Pain, 2 (1983) 189-195.

8 Handwerker, H.O., Iggo, A. and Zimmermann, M., Segmental and supraspinal actions on dorsal horn

neurons responding to noxious and non-noxious skin stimuli, Pain, 1 (1975) 147-165.

9 Hansson, P. and Ekblom, A., Transcutaneous electrical nerve stimulation (TENS) as compared to

placebo TENS for the relief of acute oro-facial pain, Pain, 15 (1983) 157-165.

10 Hosobuchi. Y.. Adams, J.E. and Linchitz, R., Pain relief by electric stimulation of the central gray

matter in humans and its reversal by naloxone, Science, 197 (1977) 183-186.

11 Iwamoto, E.T. and Martin, W.R., Multiple opioid receptors, Med. Res. Rev., 1 (1981) 411-440. 12 Kolmodin, G.M. and Skoglund, C.R., Analysis of spinal interneurons activated by tactile and

nociceptive stimulation, Acta physiol. stand., 50 (1960) 337-355. 13 Levine, J.D.. Gordon, N.C., Jones, R.T. and Fields, H.L.. The narcotic antagonist naloxone enhances

clinical pain, Nature (Lond.), 272 (1978) 826-827.

14 Levine, J.D., Gordon, N.C. and Fields, H.L.. Naloxone dose dependently produces analgesia and

hyperalgesia in postoperative pain, Nature (Lond.), 278 (1979) 740-741. 15 Lindblom, U. and Tegner, R., Are the endorphins active in clinical pain states? Narcotic antagonism

in chronic pain patients, Pain, 7 (1979) 65-68. 16 Lord, J.A.H., Waterfield, A.A.. Hughes, J. and Kosterlitz, H.W., Endogenous opioid peptides;

multiple agonists and receptors, Nature (Lond.), 267 (1977) 495-499.

329

17 Lundeberg, T., Naloxone does not reverse the pain-reducing effect of vibratory stimulation, Acta

anaesth. stand., 29 (1984) 212-216. 18 Lundeberg, T., Vibratory stimulation for the alleviation of chronic pain, Thesis, Acta physiol. stand.,

Suppl. 523 (1983).

19 Mayer, D.J., Price, D.D. and Rafii, A., Antagonism of acupuncture analgesia in man by the narcotic

antagonist naloxone, Brain Res., 121 (1977) 368-372.

20 Melzack, R. and Wall, P.D., Pain mechanisms: a new theory, Science, 150 (1965) 971-979.

21 Meyerson, B.A., Electrostimulation procedures: effects, presumed rationale and possible mechanisms.

In: J.J. Bonica, U. Lindblom and A. Iggo (Eds.), Advances in Pain Research and Therapy, Vol. 5,

Raven Press, New York, 1983, pp. 495-534.

22 Ottoson, D., Ekblom, A. and Hansson, P., Vibratory stimulation for the relief of pain of dental origin,

Pain, 10 (1981) 37-45.

23 Pertovaara, A. and Kemppainen, P., The influence of naloxone on dental pain threshold elevation

produced by peripheral conditioning stimulation at high frequency, Brain Res., 215 (1981) 426-429.

24 Pertovaara, A., Kemppainen, P., Johansson, G. and Karonen, S.-L., Dental analgesia produced by

non-painful, low frequency stimulation is not influenced by stress or reversed by naloxone, Pain, 13

(1982) 379-384.

25 Pomeranz, B. and Cheng, R., Suppression of noxious responses in single neurons of cat spinal cord by

electroacupuncture and its reversal by the opiate antagonist naloxone, Exp. Neural., 64 (1979)

327-341.

26 Salar, G., Job, I., Mingrino, S., Bosio, A. and Trabucchi, M., Effect of transcutaneous electrotherapy

on CSFP-endorphin content in patients without pain problems, Pain, 10 (1981) 169-172.

27 Sessle, B.J., Hu, J.W., Dubner, R. and Lucier, G.E., Functional properties of neurons in cat trigeminal

subnucleus caudalis (medullary dorsal horn). II. Modulation of responses to noxious and non-noxious

stimuli by periaqueductal gray, nucleus raphe magnus, cerebral cortex and afferent influences, and

effect of naloxone, J. Neurophysiol., 45 (1981) 193-207.

28 Sjolund, B.H. and Et&son, M.B.E., The influence of naloxone on analgesia produced by peripheral

conditioning stimulation, Brain Res., 173 (1979) 295-301.

29 Sjolund, B., Terenius, L. and Eriksson, M., Increased cerebrospinal fluid levels of endorphins after

electro-acupuncture, Acta physiol. stand., 100 (1977) 382-384.

30 Woolf, C.J., Mitchell, D., Myers, R.A. and Barrett, G.D., Failure of naloxone to reverse peripheral

transcutaneous electro-analgesia in patients suffering from acute trauma, S.Afr. med. J., 53 (1978) 179-180.