Applications of Transcutaneous Electrical Nerve Stimulation in the Management of Patients with Pain State-of-the-Art Update MERYL ROTH GERSH and STEVEN L. WOLF

Numerous publications devoted to the topic of transcutaneous electrical nerve stimulation (TENS) have appeared since the presentation of a special issue of PHYSICAL THERAPY (December, 1978). This update article addresses contemporary information on efficacy, mode of application, treatment outcomes, and neuro-physiological mechanisms relevant to this modality. Investigators have become far more specific when presenting this information in the current literature on treating acute pain conditions with TENS than they were in the literature for the 1978 special issue. Improvement has been made in providing specific details to enable replication of TENS stimulating characteristics among patients with chronic pain; yet several clinical researchers still fail to evaluate treatment outcomes adequately. Perhaps the greatest advances in our understanding of TENS involve the recent development of mechanisms that might account for how different types of TENS work. Suggestions for predicting patient responses to TENS and for avenues of future inquiry are offered.

Key Words: Electric stimulation, Pain, Physical therapy.

A wealth of information is available on the clinical application of transcuta­neous electrical nerve stimulation (TENS) for pain management. In recent years, clinicians have studied the effect of TENS on pain associated with spe­cific pathological conditions and have sought a relationship between specific treatment protocols and outcomes. Au­thors have more closely attended to the importance of specific electrode place­ments and stimulation characteristics, so that studies on particular diagnostic groups of patients could be compared and replicated. More sophisticated pain evaluation tools have been used to assess a patient's response to TENS therapy.

The purpose of this article is to review critically literature about TENS, which has been generated after the publication of a special issue on TENS in PHYSICAL THERAPY in 1978, to determine if more definitive information is available re­garding 1) the efficacy of treatment for specific diagnostic categories, 2) current methods of application (specific elec­

trode placements and stimulation char­acteristics) and their effects on treatment outcomes, and 3) neurophysiological modes of action. Topics for future clin­ical study will also be discussed.

TRANSCUTANEOUS ELECTRICAL NERVE STIMULATION FOR ACUTE PAIN

One of the most successful applica­tions of TENS is for postoperative pain control.1-11 Although treatment proto­cols vary between different studies, im­portant treatment variables are fairly consistent among these studies.1 Pa­tients are generally provided with a pre­operative exposure to TENS to choose comfortable stimulation settings. Sterile electrodes are placed adjacent to the in­cision in surgery, and TENS treatment commences in the recovery room, with the stimulation variables set at a previ­ously established comfort level. Trans­cutaneous electrical nerve stimulation is used continuously for the first 48 to 72 hours; the patient regulates the stimulus intensity to suit his needs. Treatment outcomes are measured not only by sub­jective pain report, but also by the type and amount of pain medication re­quested by the patient. Incidences of postoperative ileus and atelectasis, re­cords on compliance with respiratory therapy regimens, and length of inten­

sive care and hospital stay also provide objective measures of the patient's re­sponse to TENS treatment.

Schomburg and Carter-Baker evalu­ated the analgesic effect of TENS on 75 postlaparotomy patients.2 In comparing these patients with a matched control group by retrospective chart observa­tion, the authors found that patients using TENS postoperatively required 56 percent fewer doses of pain medication during the first five postoperative days than did patients in the control group. Patients receiving TENS were more mo­bile and participated in breathing exer­cises earlier than their control group counterparts.

Ali et al studied the pulmonary func­tion of 40 patients who had undergone cholecystectomies.3 Fifteen patients used TENS continuously for the first 48 hours postoperatively and then on an "as needed" basis. Another 15 patients did not use TENS, and a third group of 10 patients used TENS units with the batteries reversed so that no current was delivered to the patient (sham TENS). Spirometric evaluations of all patients conducted on the third and fifth post­operative days indicated that patients who were treated with TENS had signif­icantly higher vital capacities and func­tional residual capacities than patients receiving either sham TENS or no TENS. Patients using TENS had a sig­nificantly decreased incidence of post-

Mrs. Gersh is a physical therapist at St. Luke's Memorial Hospital, S 711 Cowley St, Box 288, Spokane, WA 99210.

Dr. Wolf is Associate Professor, Department of Rehabilitation Medicine, Emory University School of Medicine, 1441 Clifton Rd, NE, Atlanta, GA 30322 (USA) and a senior investigator, Emory Uni­versity Rehabilitation Research and Training Cen­ter, Atlanta, GA.

Address all correspondence to Dr. Wolf. This invited paper was submitted July 16, 1984,

and was accepted September 7, 1984.

314 PHYSICAL THERAPY

PRACTICE

operative pulmonary dysfunction and complications. Patients in all groups re­quired supplemental pain medications, but those patients in the TENS group required less pain medication than did those not receiving actual TENS treat­ment.

Taylor and associates conducted a similar study with patients who had undergone abdominal surgery.4 Thirty patients used actual TENS and 22 pa­tients used sham units for one hour every four hours for the first three post­operative days. Patients were permitted to request pain medication after 30 min­utes of TENS treatment if the treatment did not adequately control pain. Twenty-five patients served as a control group. Taylor and associates noted that patients receiving TENS or sham TENS required less pain medication and am­bulated earlier than did those patients in the control group.4 The results high­lighted the placebo potential of TENS but may also be explained by the non-continuous mode of TENS application.

Another study examined the analgesic effect of TENS on patients who had undergone upper abdominal surgery.6

The patients who used TENS for post­operative pain control required 30 times less pain medication than did those in the control group. Improved pulmonary function, appetite, and ambulation in­dicated an earlier recovery for those pa­tients who used TENS than for those patients who did not. Because the report of this study lacked information on treatment protocol and technique, rep­licating or comparing these results with similar studies is impossible.

Several investigators have studied the efficacy of TENS for management of postlaminectomy pain.7-9 In all these studies, electrodes were placed parallel to the incision, stimulation was set at comfortable levels, TENS was used con­tinuously for at least the first 24 to 48 hours, and the treatment was discontin­ued after that period at each patient's request. The investigators all reported a significant decrease in the strength and amount of pain medication requested by the patients using TENS in compar­ison with those patients not using TENS. Solomon et al reported that TENS appeared most effective in "drug-naive" patients, those who had not used narcotics preoperatively for more than two weeks in the six months before sur­gery.7 Furthermore, they noted that poor pain relief was reported by drug-

experienced patients, regardless of whether TENS or narcotics were used. This occurrence may suggest a cross-tolerance between narcotics and TENS and activation of a similar neural sub­strate to explain the analgesic effect of both TENS and opioid derivative med­ications.

Richardson and Siquiera carefully re­corded the stimulation settings used.8

They observed no correlation between specific pulse widths, rates, or stimulus intensities and the degree of pain relief reported. Other investigators have cor­roborated this finding.12

Additional benefits of postoperative pain management with TENS may be realized by the postcesarean patient. Nonnarcotic pain control by use of TENS may facilitate earlier mother-in­fant bonding. Drug-induced side effects such as nausea, drowsiness, and respi­ratory depression are limited. Narcotics are not passed to the baby by breast­feeding. Pulmonary rehabilitation is fa­cilitated and reduces the occurrence of pulmonary complications in the mother.10

Harvie cited rehabilitation benefits when using TENS to control postoper­ative pain after knee surgery.11 He stud­ied patients who had undergone total knee replacements, synovectomies, meniscectomies, arthrotomies, patch­plasties, or fracture reductions. Elec­trodes placed over the medial and lateral collateral ligaments provided the most effective pain control. Narcotic use was decreased by 75 to 100 percent. Recov­ery of quadriceps femoris muscle strength and knee range of motion (ROM) was facilitated. Four of seven patients with total knee replacements achieved 80 to 90 degrees of active knee flexion by the sixth postoperative day; the other three patients achieved the same goal by the eighth postoperative day. Earlier ambulation and decreased length of hospital stay were also re­ported. Clearly, TENS for management of postoperative knee pain is an impor­tant adjunct to a rehabilitation program.

Transcutaneous electrical nerve stim­ulation can also be applied for control of acute dental pain.13, 14 Hansson and Ekblom evaluated 62 patients admitted to an emergency dental clinic with acute pain secondary to pulpal inflammation, apical periodontitis, or postoperative pain after tooth extraction.13 Patients were randomly assigned to one of three groups: those receiving high frequency

TENS (100 Hz; n = 22); those receiving low frequency TENS (2 Hz; n = 20); and those receiving a placebo treatment (batteries removed from the unit; n = 20). Electrodes were placed on the face over the painful area. Stimulus intensity was set to three times the sensory thresh­old for patients in the high frequency group, and three to five times sensory threshold for those receiving low fre­quency TENS. This latter group expe­rienced muscular contractions associ­ated with the higher intensity. Patients used a visual analog scale to record their pain intensity before, during, and after treatment. Seven of 22 patients (31.8%) in the high frequency group reported pain relief of greater than 50 percent after 30 minutes of treatment, compared with 9 of 20 patients (45%) in the low frequency group, and 2 of 20 (10%) in the placebo group. Pain returned within 10 minutes after treatment in 4 of 7 patients in the high frequency group, and in 2 of 9 patients in the low fre­quency group. The 2 patients in the placebo group who reported initial relief experienced longer lasting relief. Two other patients in the high frequency group and 2 in the low frequency group reported complete pain relief after treat­ment. Differences in the analgesic effec­tiveness of TENS demonstrated between the high and low frequency groups were not significant. The effectiveness of TENS for pain control, however, was significantly greater when either experi­mental group was compared with the placebo group. Pain control of longer duration might have occurred if treat­ment duration could have been longer than 30 minutes.

Transcutaneous electrical nerve stim­ulation is being used, especially outside of the United States, to control acute pain associated with labor and deliv­ery.15, 16 Erkola et al evaluated 100 pa­tients who used TENS for pain manage­ment during the first stage of labor.15

Electrodes were placed paravertebrally at T10-11 and S2-4. Stimulus intensity was set at a tolerable submotor threshold and regulated by the patient. Thirty-one percent of the patients reported good pain relief, and 55 percent reported moderate relief within one hour of ini­tiating treatment. Details of the pain rating procedure were not described. Pa­tients using TENS, however, requested a similar amount of pain medication during labor in comparison with a con­trol group who did not use TENS.

Volume 65 / Number 3, March 1985 315

Jones reported that 82 percent of the patients in labor using TENS had sub­stantial relief of back labor pain and 71 percent had significant relief of abdom­inal labor pain during the first stage of labor.16 Again, methods used to measure pain were not described. During the sec­ond stage of labor, TENS was frequently discontinued because it interfered with the patient's controlled breathing and pushing efforts. Transcutaneous electri­cal nerve stimulation also interfered with continuous fetal monitoring. The use of TENS did not affect the length of labor or immediate postnatal health of the infant.

Further investigation of the role of TENS in the management of labor pain is warranted with close attention paid to application techniques and measure­ment of treatment outcome. Reduction of the need for narcotics during labor could contribute to the improved peri­natal and postnatal health of the mother and the improved respiratory and neu­rological status of the newborn child.

Methods of application for TENS to control acute pain are summarized in Table 1. All but one report provide spe­cific electrode placements for particular pain locations. Ranges are given most

frequently to describe stimulation set­tings used, and the frequency and du­ration of TENS treatment is reported. The provision of application details in recent literature allows more accurate comparison and replication of clinical research.

Table 2 summarizes the evaluation tools used to assess TENS treatment outcomes for acute pain management. A variety of subjective pain rating scales and recording of pain medication intake were used most commonly to assess the analgesic effect of TENS. In three stud­ies, additional credence was given to favorable treatment outcomes by use of objective physical evaluations, such as pulmonary function studies or joint range-of-motion measurements. In ad­dition to the patients' reports of pain, objective evaluation procedures en­hance the reliability and validity of these clinical studies.

Recent literature has been favorable on the efficacy of TENS for acute pain control. The location and description of acute pain is usually precise and allows for use of a more specific treatment approach. Homogeneous groups of pa­tients (eg, those with postoperative pain) and matched control groups are readily

available for evaluation. Treatment out­comes may be objectively measured in terms of medication intake, respiratory status, rehabilitation factors, and subjec­tive pain ratings. These advantages are not as readily available when studying the management of chronic pain and may explain the wide variation in re­sponse to TENS treatment among chronic pain patients.

TRANSCUTANEOUS ELECTRICAL NERVE STIMULATION FOR CHRONIC PAIN

Studies examining patients with widely divergent diagnoses or symptom complexes are not as prevalent in the TENS literature today as they were sev­eral years ago. These studies can provide valuable information in selecting which diagnostic groups of patients respond most favorably to TENS for pain relief.

Wolf and colleagues evaluated the re­sponses to TENS of 114 patients with chronic pain.12 Patients reported pain secondary to peripheral neuropathy, pe­ripheral nerve injury, radiculopathy, or musculoskeletal trauma. Electrodes were systematically placed at the painful

TABLE 1 Transcutaneous Electrical Nerve Stimulation Application Methods for Acute Pain

Primary Author

Schomburg2

Ali3

Taylor4

Sodipo6

Solomon7

Richardson8

Schuster9

Riley10

Harvie11

Hansson13

Erkola15

Jones16

Diagnosis

postlaparotomy

postcholecys­tectomy

postlaparotomy postlaparotomy postoperative

postlaminectomy

postlaminectomy

postcesarean section

postoperative knee pain

dental pain

labor pain

labor pain

Electrode Placement

parallel to incision

parallel to incision

parallel to incision parallel to incision 1.0 cm parallel to

incision 5 cm parallel to

incision

2.5 cm parallel to incision

above and below incision

over medial and lateral collateral ligaments

over painful site

paraspinal T10-L1, S2-S4

Pulse Width (µ see)

120-340

128-200

80

72.5-240.0

40-100

250-400

200

84

Pulse Rate (PPS)

10-100

10-100

40

8.7-240

25-100

80-100

100

2

Intensity

0-90 V (comfort)

0-135 mA (comfort)

comfort

0.2-38.5 mA

0-90 V

20-35 mA

comfort

2-3 times sensory threshold or

3-5 times sensory threshold

20-25 V (comfort)

comfort

Frequency and Duration of Treatments

constant for first 48 hr, then as needed

constant for first 48 hr

60 min every 4 hr

constant for first 48 hr

within first 20 hr post­operatively, for 3-12 days

constant for first 18-24 hr

constant, or 30 min four times a day

30 min

30 min

during first stage of labor

during first stage of labor

316 PHYSICAL THERAPY

PRACTICE

TABLE 2 Evaluation Methods for Transcutaneous Electrical Nerve Stimulation Treatment for Acute Pain

Primary Author

Schomburg2

Ali3

Taylor4

Sodipo6

Solomon7

Richardson8

Schuster9

Riley10

Harvie11

Hansson13

Erkola15

Jones16

Diagnosis

postlaparotomy

postcholecys­tectomy

postlaparotomy postlaparotomy postoperative postlaminectomy

postlaminectomy

postcesarean section

postoperative knee pain

dental pain labor pain labor pain

Subjective Pain Rating

yes

no

yes no yes yes

yes

yes

no

yes yes yes

Pain Medication Taken

yes

yes

yes yes yes yes

yes

yes

yes

no yes yes

Physical Evaluations

spirometry, arterial blood gases

pulmonary functions

none

none

none

knee range of mo­tion, straight leg raise, early ambu­lation

none none none

Other

resumption of ac­tivities

postoperative complication

resume ambulation resume ambulation

length of hospital stay

postoperative complication

site or on related nerve roots or periph­eral nerves. Stimulation variables were set to evoke a strong but comfortable sensation in the painful region, and ex­act electrical settings were recorded. Treatments were conducted on an out­patient basis and were of 30- to 45-minute duration. Patients rated their pain intensity on a 10-cm line before, during, and immediately after treat­ment. In addition, some patients com­pleted the pain descriptor word list found in the McGill Pain Question­naire.17 Thirteen of 18 patients (72%) with peripheral neuropathy, 6 of 21 pa­tients (28.5%) with peripheral nerve in­jury, 8 of 36 patients (22%) with radic­ular pain, and 15 of 39 patients (38.4%) with musculoskeletal pain reported more than 60 percent relief of pain after TENS treatment.12 In the peripheral neuropathy group, patients with post­herpetic neuralgia responded most favorably to TENS. Patients with fewer previous analgesic treatments, no sur­gical intervention, and limited narcotic use responded more favorably than those patients with numerous previous treatments. We found no significant re­lationship between specific electrode placements or stimulation settings and treatment outcomes, but patients with radiculopathy or peripheral nerve injury responded better to higher intensity stimulation. This observation was also reported by Melzack in treating patients with chronic low back pain.18 Follow-

up evaluations on 25 patients who used TENS at home for one month generally indicated decreased benefits from treat­ment as time progressed. These de­creased benefits may have been due to reduced patient compliance when inde­pendent TENS application became a requirement.

Another investigation studied 98 pa­tients with back pain, headache, or a variety of other pain symptoms.19 Pa­tients used TENS at home, placing elec­trodes at the site of pain, and setting stimulation intensity at a comfortable level. Patients recorded their own sub­jective pain level before and after treat­ment. After 12 days of home treatment, 69 percent of the patients with low back pain, 40 percent of those with headache pain, and 60 percent of those with pain from other sources reported more than 50 percent relief of pain. The authors failed to describe stimulation settings, pain-rating measures, and duration and frequency of treatment; they also did not control for a wide variation in ap­plication techniques based on patient competence and compliance. Thus, this study provided little valuable informa­tion on TENS for chronic pain control.

Santiesteban described the use of low frequency TENS (2-4 Hz) for treatment of spinal pain.20 Stimulus pulse width was set at the maximum for the units used, and intensity was set at 50 mA to evoke a muscle contraction within pain tolerance. Electrodes were placed 2.5 to

5 cm from the appropriate spinous proc­ess in a parallel or crossed configuration. Distal acupuncture points were also stimulated. Patients required less anal­gesic medication when TENS was used to control pain.

Melzack and colleagues recently com­pared the analgesic effects of TENS and massage in a double-blind study of 41 patients with chronic low back pain.21

Transcutaneous electrical nerve stimu­lation electrodes were placed in the cen­ter of the back and on the lateral thigh. Low frequency stimulation (4-8 Hz) with a strong but tolerable intensity was applied. The massage was performed with a suction cup apparatus. Treatment was given two times a week for 30 min­utes, for a maximum of 10 treatments. Treatment outcomes were evaluated us­ing both the present-pain intensity (PPI) scale and the pain-rating index of the McGill Pain Questionnaire.17 Bilateral straight leg raising (SLR) and lumbo­sacral flexion were also measured. Transcutaneous electrical nerve stimu­lation produced a significantly greater improvement than massage in the pain-rating and the PPI scales and in the bilateral SLR measures for these pa­tients.21

Transcutaneous electrical nerve stim­ulation has been used with various de­grees of success in the management of arthritic pain. Taylor et al evaluated the effect of TENS on osteoarthritic knee pain.22 Patients used actual TENS or a

Volume 65 / Number 3, March 1985 317

TABLE 3 Transcutaneous Electrical Nerve Stimulation Application Methods for Chronic Pain

Primary Author

Wolf12

Moore19

Santiesteban20

Melzack21

Taylor22

Winnem27

Kahn29

Gersh24

Diagnosis

varied

varied

spine pain

low back pain

osteoarthritis of knee

phantom limb pain

nonunited fracture

peripheral neuropa­thy

Electrode Placement

site of pain, related nerve roots, or peripheral nerve

varied

paravertebral

center of back and lateral thigh

about knee

stump or contralat­eral limb

over fracture site in crossed pat­tern

along nerve trunk at site of pain

Pulse Width (µ sec)

100

midrange

maximum

300

200

Pulse Rate (pps)

50-100

10-100 or 1-4

2-4

4-8

comfort

100 or 2

minimum

110

Intensity

submotor threshold

comfort

motor threshold (50 mA)

to tolerance

comfort

sensory threshold (less than 20 mA)

26-28 mA

Frequency and Duration of Treatments

30-45 min, 3-5 times a week

30-60 min daily or as needed

30-60 min

30 min, 2 times a week

30-60 min as needed

15 min twice a day

30-60 min, 3-4 times a day

continuous, 8-10 hr a day

placebo unit wired to produce various sounds in a well-monitored home pro­gram. After two weeks of home treat­ment, patients were reevaluated and sent home to use the other (TENS or placebo) unit for another two weeks. Patients were evaluated again and per­mitted to take home the most beneficial unit for one more month of home treat­ment. Responses to treatment were eval­uated by subjective pain rating, ambu­lation distance, and analgesic medica­tion intake. The actual TENS provided significantly more pain relief than did the placebo unit in both subjective and medication analyses. Patients reported the greatest pain relief while wearing the active TENS unit. Relief frequently lasted for several hours after treatment was completed. Several patients contin­ued to use the TENS at home for several months. They reported decreasing pain relief over time, possibly because of in­creasing joint deterioration.

Transcutaneous electrical nerve stim­ulation may be an important adjunct in the rehabilitation of arthritic patients, particularly when joint replacement is not possible. In patients with chronic systemic diseases who may be receiving a variety of pharmacologic and thera­peutic treatments concurrently, the cli­nician must be alert, however, to ad­verse reactions to TENS, as reported by Griffin and McClure.23

Patients with a variety of peripheral neuropathic conditions including pe­ripheral neuropathy,24 postherpetic neu­ralgia, peripheral nerve injury, reflex sympathetic dystrophy,25 and Sudeck's atrophy26 have all responded favorably to TENS treatment. Transcutaneous electrical nerve stimulation has also proven effective in the management of phantom limb pain27 and the distal burning paresthesia associated with Guillain-Barré syndrome.28

Kahn provided radiographic evidence that TENS facilitated callous formation and osseous bridging at sites of non-united fractures in three patients.29

Transcutaneous electrical nerve stimu­lation was originally applied to control pain in these patients for nonunited fractures six months after injury. Elec­trodes were placed in various configu­rations to "sandwich" the fracture site. Pulse width was set for the longest "on" time, pulse rate was set at the lowest available frequency, and stimulus inten­sity was set at the sensory threshold. Increased callous formation was noticed on radiographic examination after one month of treatment in one patient and after 10 weeks of treatment in the other two patients.

Millea described another unusual ap­plication of TENS.30 A 50-year-old pa­tient with an eight-year history of non-operative abdominal pain and disten­

tion was relieved of this discomfort after using TENS for five days. This relief may be attributed to decreased sympa­thetic tone and increased gastric motility associated with TENS application.31

Owens et al observed local vasodila­tion and skin temperature increases of 1°C when TENS was applied at the ulnar groove and wrist in seven healthy sub­jects.31 Such evidence also may explain the mechanism of pain relief in patients with causalgia or reflex sympathetic dys­trophy. Consistent sympathetic nervous system responses, however, have not, as yet, been recorded among a variety of patients.25

Table 3 summarizes the application procedures used for chronic pain control with TENS. Significant effort has been made by most investigators in recent years to specify effective electrode place­ments and stimulating settings. Al­though specific pulse widths, rates, and intensities are not always cited, most reports provide a description of the sen­sory or motor responses elicited by TENS during treatment. Treatment du­ration was usually 30 to 60 minutes, but the frequency of treatment varied with each study. Replication of clinical stud­ies is facilitated when these procedures are described in detail.

Perhaps the weakest aspect of the clin­ical study of TENS for chronic pain control is evaluation of treatment out-

318 PHYSICAL THERAPY

PRACTICE

comes. Table 4 illustrates that most in­vestigators still rely solely on the pa­tient's report of pain to establish the efficacy of TENS treatment. Often, the pain-rating scale used by the patient is not described in detail. The great variety of pain symptoms, locations, previous and concomitant treatments, medica­tions, and psychological components as­sociated with chronic pain make objec­tive evaluation much more difficult than in patients with acute pain. Use of physical measures, such as joint motion, strength, muscle girth, and participation in functional activities, however, would enhance the objective evaluation of the efficacy of TENS for chronic pain con­trol.

PREDICTING RESPONSE TO TRANSCUTANEOUS ELECTRICAL NERVE STIMULATION TREATMENT

Successful use of TENS for pain con­trol may be increased as more specific patient evaluation and selection criteria are established. Reynolds and associates examined the predictive value of pain questionnaires in selecting patients who would be more likely to respond favor­ably to TENS treatment.32 Their evalu­ation indicated that older, retired pa­tients, who had pain of less than one year duration, who had undergone lim­ited or no surgery, and who used non­narcotic analgesics were more likely to experience pain relief with TENS. Site

of injury, sensory deficit, and secondary gain by financial compensation for in­jury did not affect response to treat­ment. The pain questionnaire, however, seemed to have less predictive value for TENS than for other treatment regi­mens.

In another study, Johansson et al sug­gested that patients with neurogenic pain responded more favorably to TENS than did patients with somato­genic or psychogenic pain.33 Patients with pain in the extremities seemed to derive more relief with TENS than pa­tients with axial pain. The patient's age, sex, and pain intensity did not relate to his response to treatment.

Richardson and colleagues explained how treatment with TENS could con­firm a diagnosis of functional pain com­pared with organic pain.34 Many pa­tients with suspected functional pain re­ported increased pain during and after TENS treatment. Pain was relieved with a saline injection in the majority of these patients.

Mannheimer compiled a list of factors that hinder, enhance, or restore the ef­fectiveness of TENS for pain control.35

Among those factors that enhance TENS effectiveness are careful, contin­uous patient evaluation for most effec­tive electrode placement sites and stim­ulation settings; changing stimulation modes and characteristics; gradually in­creasing patient tolerance to stronger stimulation in the painful area; elec­

trode placement on motor points or su­perficial aspects of nerves; weaning pa­tients from addictive medications before treatment; and educating the patient in the proper use of the modality for home treatment. Incorporating these selection and treatment criteria into treatment protocols and recording which patients most favorably respond to TENS will increase the successful use of this mo­dality in the future.

NEUROPHYSIOLOGICAL MODES OF ACTION

Several years ago, the options avail­able to explain the possible neurophysi­o l o g y mechanisms through which TENS could affect pain perception were limited.36 The prevailing explanation for most pain attenuating interventions cited the spinal gate concept developed by Melzack and Wall in 1965.37 Briefly, this notion took into account existing electrophysiological data from animal experiments that had demonstrated dif­ferential effects of collateral axons from large diameter afferent fibers mediating touch and pressure and from small di­ameter afferent fibers conveying noci­ceptive input upon interneurons within the substantia gelatinosa (Fig. 1). These interneurons could be facilitated through predominantly large diameter collateral afferent input and inhibited through primarily collateral axons from the small diameter system. In addition, the interneuron was inhibitory onto the

TABLE 4 Evaluation Methods for Transcutaneous Electrical Nerve Stimulation Treatment for Chronic Pain

Primary Author

Wolf12

Moore19

Santlesteban20

Melzack21

Taylor22

Winnem27

Kahn29

Gersh24

Diagnosis

varied

varied spine pain low back

pain

osteoarthritis of knee

phantom limb pain

nonunited fracture

peripheral neuropa­thy

Subjective Pain Rating

McGill Pain Question­naire

yes no McGill Pain

Question­naire

yes

yes

yes

yes

Pain Medication Taken no

no yes no

yes

no

no

no

Physical Evaluations

none

none none straight leg raise,

lumbosacral range of mo­tion

roentgenogram, ambulation distance

none

roentgenogram

none

Other

resume functional activities

Volume 65 / Number 3, March 1985 319

Periphery Spinal Cord Lamina II & III

Spinal Cord Lamina V

Fig. 1. Schematic diagram depicting the Melzack-Wall gate theory of pain. Open circles represent facilitator/ synapses; closed circles indicate inhibitory synapses. Abbreviations SG = substantia gelatinosa; T = transmission cells.

terminals of both afferent fiber classes. Consequently, when large diameter afferent fiber activation was of greater frequency and intensity than smaller diameter fiber input, the inhibitory interneurons would be activated to presynaptically inhibit transmission centrally from both the noxious and nonnoxious inputs. The gate would be closed. Of course, the opposite effect would predominate if greater transmis­sion occurred through the smaller di­ameter system.

This gating theory was subjected to considerable criticism because it con­ceptually failed to account for pain relief among a variety of clinical conditions. Nonetheless, the test of time has proven that the framework for the theory has formed the basis for several more con­temporary explanations of pain allevia­tion through TENS. Specifically what the Melzack-Wall model brought to the attention of scientists and clinicians was the recognition that pain perception could be modulated somewhere within the neuraxis if the appropriate stimuli could be delivered and the appropriate neural substrate on which such stimuli might act could be found.

A spinal gate that conceptually fol­lows the original model might incorpo­rate conventional TENS (low intensity, high frequency stimuli) to effect pain reduction among patients with a diag­nosis of postherpetic neuralgia. This dis­ease process causes selective degenera­tion among large diameter peripheral axons. The success with conventional TENS may reside in the activation of

remaining large afferent fibers or those in close proximity to the painful site but which enter the neuraxis at the same or nearby segments as the ongoing noxious input.38 A similar explanation may be appropriate to explain how pain follow­ing certain kinds of peripheral nerve injury may respond to conventional TENS.39

Recently, clinicians have recognized that conventional TENS may not be the most effective form of stimulation for certain types of chronic pain. This thought was promoted when Ericksson and co-workers identified a large group of patients with chronic pain who showed further improvement in reduced pain perception when conventional TENS was supplemented by acupunc­ture-like TENS (low frequency, high in­tensity stimulation).40 This latter form of stimulation showed effects that were reversible through the administration of the opioid antagonist, naloxone hydro­chloride; this reversal suggests that the

effects of acupuncture-like TENS might be mediated through an endogenous opiate system within the neuraxis.41 Pre­viously, Mayer and colleagues had dem­onstrated that the effectiveness of acu­puncture was also reversed by naloxone hydrochloride.42 These clinical findings prompted a comprehensive search for the neural substrates mediating the re­sponsiveness of chronic pain patients to high intensity cutaneous stimulation.

At the same time, a variety of opiate receptors and numerous loci of endog­enous opiates were being discovered in many human and subhuman primate studies.43 A logical marriage from this exponentially increasing body of knowl­edge resided in establishing relationships between neurophysiological and neu-rohistochemical studies on pain mech­anisms and opiate substances, respec­tively. The mechanism first proposed by Basbaum and Fields in 1978 served to collate known histochemical and phys­iological data to explain how high inten­sity cutaneous electrical stimulation (for example, acupuncture-like TENS, brief-intense TENS, or burst trains of TENS) might activate endogenous opiates to alleviate pain.44

This modulatory mechanism is essen­tially a negative feedback loop that is schematically illustrated in Figure 2. Ongoing pain input and the discomfort often associated with high intensity TENS activate ascending pathways lead­ing to conscious awareness of pain. Cer­tain axons within the ascending system are known to form a synapse within medullary reticular formation nuclei, and from these nuclei, this input is transmitted to the periaqueductal gray region of the midbrain (mesenceph­alon). This location is exceptionally en­dowed with high concentrations of en­dogenous opiates, and when it is acti­vated, either through natural cutaneous

Central Nervous System

Fig. 2. Schematic diagram of negative feedback loop within the neuraxis activated by noxious input.

320 PHYSICAL THERAPY

PRACTICE

stimulation, iontophoretically applied morphine, or through direct stimula­tion, its efferent axons form a synapse with nuclei (raphe magnus and reticu­laris magnocellularis) within the me­dulla oblongata. Output from these nu­clear groups descends through the dor­solateral funiculus of the spinal cord to make enkephalinergic synapses known to inhibit the spinal transmission of Sub­stance P, a polypeptide implicated as a neurotransmitter between axons con­veying noxious information.45 This last neural interaction completes the nega­tive feedback loop to modulate ongoing or subsequent noxious input. For fur­ther details, please refer to the Pain: Mechanism: B. Basic section within the Bibliography.

Another mechanism that may ac­count for some aspects of pain modu­lation with TENS involves what LeBars et al have termed "diffuse noxious in­hibitory controls," or DNIC.46 Within this system, responses elicited through continuous pain input to convergent dorsal horn neurons may be suppressed effectively by noxious or intense cuta­neous stimulation, when it is applied almost anywhere on the body surface. Responses obtained through activity within the small diameter afferent fiber groups are inhibited, but nonnoxious activation of the same convergent cells or nonconvergent cells responsive to only noxious stimuli remain unaffected. Within animal models, spinalization eliminates DNIC, thereby suggesting that descending supraspinal influences are required to activate this system. Fur­thermore, the DNIC mechanism is sen­sitive to naloxone hydrochloride; this sensitivity indicates an endorphin link.47

Whether this linkage occurs at spinal or supraspinal levels has yet to be deter­mined. Also, definitive data to test the validity of the DNIC model in man have yet to be presented.

Nonetheless, the mechanisms de­scribed in this article form plausible ex­planations for the way in which high intensity TENS might modulate pain perception. Other mechanisms have been proposed, but both the quantity and quality of research led us to refrain from addressing these in this article. Un­doubtedly, as more data evolve and his-tochemical and electrophysiological techniques gain sophistication, addi­tional ways of speculating on or com­prehending how TENS modulates pain perception will be forthcoming.

AREAS FOR FUTURE STUDY

To facilitate the continued effective use of TENS for pain control, several areas of study must be pursued. Patient evaluation and selection criteria should be validated and refined to increase suc­cessful treatment with TENS, particu­larly in patients who have chronic pain. Specific electrode placements and stim­ulation characteristics must be evalu­ated in relation to specific disease enti­ties to establish more effective treatment protocols. Clinicians should continue to evaluate the benefits of high versus low frequency stimulation, auriculother-apy,48 and acupuncture point stimula­tion. Use of TENS for acute pain con­trol should be expanded within areas where it is apparently effective (eg, post­operative pain, labor and delivery pain, and pain from acute injury48). Adverse

responses to treatment such as contact dermatitis49, 50 should be reported so that hypoallergenic materials can be devel­oped in the manufacturing of electrodes and conductive media, and so that pa­tients at high risk for negative responses to treatment may be screened.23 Ongo­ing evaluation of long-term use of TENS by chronic pain patients may yield in­formation on long-term effectiveness and clarify the neurophysiology on which treatment is based. The expand­ing body of knowledge resulting from applied and basic research on neuro­chemical and physiological bases for pain control must address the modus operandi of TENS, taking into account the stimulus characteristics applied within experimental protocols and how the relationship between stimulation and response explains the efficacy of this modality.

REFERENCES

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Volume 65 / Number 3, March 1985 321

29. Kahn J: Transcutaneous electrical nerve stim­ulation for nonunited fractures: A clinical re­port. Phys Ther 62:840-844, 1982

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31. Owens S, Atkinson ER, Lees DE: Thermo­graphic evidence of reduced sympathetic tone with transcutaneous nerve stimulation. Anes­thesiology 50:62-65, 1979

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48. Paris DL, Baynes F, Gucker B: Effects of the Neuroprobe in the treatment of second-degree ankle inversion sprains. Phys Ther 63:35-40, 1983

49. Bolton L: TENS electrode irritation. J Am Acad Dermatol 8:134-135, 1983

50. Zugenman C: Dermatitis from TENS. J Am Acad Dermatol 6:936-939,1982

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322 PHYSICAL THERAPY

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30. Meyer PG, Nashold BS, Peterson J: Di­agnosis of electric neurostimulating de­vice dysfunction. Appl Neurophysiol 42:352-364, 1979

31. Millea TP: Transcutaneous electrical nerve stimulation in the management of nonoperative intra-abdominal pain: A case report. Phys Ther 63:1280-1282, 1983

32. Miller Jones CMH: Forum: Transcuta­neous nerve stimulation in labour. An­aesthesia 35:372-375, 1980

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34. O'Brien WJ, Rutan FM, Sanborn C, et al: Effect of transcutaneous electrical nerve stimulation on human blood β-en­dorphin levels. Phys Ther 64:1367-1374, 1984

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36. Owens S, Atkinson ER, Lees DE: Ther­mographic evidence of reduced sympa­thetic tone with transcutaneous nerve stimulation. Anesthesiology 50:62-65, 1979

37. Paris DL, Baynes F, Gucker B: Effects of the neuroprobe in the treatment of second-degree ankle inversion sprains. Phys Ther 63:35-40, 1983

38. Pesschanski M, Guilbaud G, Gautron M: Posterior intralaminar region in rat: Neu­ronal responses to noxious and nonnox-ious cutaneous stimuli. Exp Neurol 73:226-238, 1981

39. Pike PMH: Transcutaneous electrical stimulation: Its use in the management of postoperative pain. Anaesthesia 33:165-171, 1978

40. Pomeranz B, Cheng R: Suppression of noxious responses in single neurons of cat spinal cord by electroacupuncture and its reversal by the opiate antagonist naloxone. Exp Neurol 64:327-341, 1979

41. Reynolds AC, Abram SE, Anderson RA, et al: Chronic pain therapy with transcu­taneous electrical nerve stimulation: Pre­dictive value of questionnaires. Arch Phys Med Rehabil 64:311-313, 1983

42. Richardson RR, Cerullo LJ: Transab­dominal neurostimulation in treatment of neurogenic ileus. Appl Neurophysiol 42:375-382, 1979

43. Richardson RR, Cerullo LJ, Raimondi AJ: Transabdominal neurostimulation in the treatment of neurogenic ileus. Paper read at Fifty-fifth Annual American Con­gress of Rehabilitation Medicine, New Orleans, LA, November 12, 1978

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46. Schneider RJ: Low temperature painful stimulus alters brain wave pattern of transcutaneous electrical stimulus. Life Sci 28:1269-1278, 1981

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50. Stanley TH, Cazalaa JA, Atinault A, et al: Transcutaneous cranial electrical stimulation decreases narcotic require­ments during neurolept anesthesia and operation in man. Anesth Analg 61:863-866, 1982

51. Stanley TH, Cazalaa JA, Limoge A, et al: Transcutaneous cranial electrical stimu­lation increases the potency of nitrous oxide in humans. Anesthesiology 57:293-297, 1982

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PAIN: MECHANISM

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3. Amano K, Tanikawa T, Kawamura H, et al: Endorphins and pain relief—fur­ther observations on electrical stimula­tion of the lateral part of the periaque­ductal gray matter during rostral mes­encephalic reticulotomy for pain relief. Appl Neurophysiol 45:123-135, 1982

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6. Brucini M, Duranti R, Galletti R, et al: Pain thresholds and electromyographic features of periarticular muscles in pa­tients with osteoarthritis of the knee. Pain 10:57-66, 1981

7. Campbell JN: Examination of possible mechanisms by which stimulation of the spinal cord in man relieves pain. Appl Neurophysiol 44:181-186,1981

8. Chao EYS: Justification of triaxial gon­iometer for the measurement of joint rotation. J Biomech 13:989-1006, 1980

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Volume 65 / Number 3, March 1985 323

11. Cram JR, Stegar JC: EMG scanning in the diagnosis of chronic pain. Biofeed­back Self Regul 8:229-241, 1983

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24. Laitinen LV: Inhibition of cutaneous no­ciception by deep musculoskeletal pain: A clinical observation. Pain 13:373-377, 1982

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28. Lindblom U, Tegner R: Are the endor­phins active in clinical pain states? Nar­cotic antagonism in chronic pain pa­tients. Pain 7:65-68, 1979

29. Long DM, Erickson D, Campbell J, et al: Electrical stimulation of the spinal cord and peripheral nerves for pain con­

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30. Malow RM, Olson RE: Changes in pain perception after treatment for chronic pain. Pain 11:65-72, 1981

31. Markoff RA, Ryan P, Young T: Endor­phins and mood changes in long-dis­tance running. Med Sci Sports Exerc 14:11-15,1982

32. Marsland AR, Weekes JWN, Atkinson RL, et al: Phantom limb pain: A case for beta blockers? Pain 12:295-297, 1982

33. Mather L, Mackie J: The incidence of postoperative pain in children. Pain 15:271-282,1983

34. Meglio M, Cioni B, Del Lago A, et al: Pain control and improvement of pe­ripheral blood flow following epidural spinal cord stimulation. J Neurosurg 54:821-823, 1981

35. Melzack R, Loeser JD: Phantom body pain in paraplegics: Evidence for a cen­tral "Pattern Generating Mechanism" for pain. Pain 4:195-210, 1978

36. Meyer RA, Campbell JN: Myelinated nociceptive afferents account for the hyperalgesia that follows a burn to the hand. Science 213:1527-1529, 1981

37. Mills KR, Newham DJ, Edwards RHT: Force, contraction frequency and en­ergy metabolism as determinants of is-chaemic muscle pain. Pain 14:149-154, 1982

38. Neumann PB, Henriksen H, Grosman N, et al: Plasma morphine concentra­tions during chronic oral administration in patients with cancer pain. Pain 13:247-252, 1982

39. Noordenbos W, Wall PD: Implications of the failure of nerve resection and graft to cure chronic pain produced by nerve lesions. J Neurol Neurosurg Psy­chiatry 44:1068-1073, 1981

40. Pertovaara A, Kemppainen P, Johans­son G, et al: Ischemic pain nonsegmen-tally produces a predominant reduction of pain and thermal sensitivity in man: A selective role for endogenous opioids. Brain Res 251:83-92, 1982

41. Pertovaara A: Modification of human pain threshold by specific tactile recep­tors. Acta Physiol Scand 107:339-341, 1979

42. Ray CD: Spinal epidural electrical stim­ulation for pain control: Practical details and results. Appl Neurophysiol 44:194-206, 1981

43. Ready LB, Sarkis E, Turner JA: Self-reported vs actual use of medications in chronic pain patients. Pain 12:285-294, 1982

44. Richelson E: Spinal opiate administra­tion for chronic pain: A major advance in therapy. Mayo Clin Proc 56:1-3, 1981

45. Roby A, Bussel B, Wilier JC: Morphine reinforces post-discharge inhibition of a-motoneurons in man. Brain Res 222:209-212, 1981

46. Rosenfeld JP, Pickrel C, Bronton JG: Analgesia for orofacial nociception pro­duced by morphine microinjection into the spinal trigeminal complex. Pain 15:145-155, 1983

47. Salter M, Brooke RI, Merskey H, et al: Is the temporo-mandibular pain and dysfunction syndrome a disorder of the mind? Pain 17:151-166, 1983

48. Schull J, Kaplan H: Naloxone can alter experimental pain and mood in hu­mans. Physiological Psychology 9:245-250, 1981

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94. Lovick TA, Wolstencroft JH: Re­sponses of medial reticular neurones to tooth pulp stimulation: Evidence for a monosynaptic input. J Physiol (Lond) 292:40-41,1979

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99. Meyer RA, Campbell JN: Evidence for two distinct classes of unmyelinated nociceptive afferents in monkey. Brain Res 224:149-152, 1981

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146. Watkins LR, Johannessen JN, Kin-scheck IB, et al: The neurochemical basis of footshock analgesia: The role of spinal cord serotonin and norepi­nephrine. Brain Res 290:107-117, 1984

147. Watkins LR, Kinscheck IB, Mayer DJ: The neural basis of footshock analge­sia: The effect of periaqueductal gray lesions and decerebration. Brain Res 276:317-324, 1983

148. Watkins LR, Mayer DJ: Involvement of spinal opioid systems in footshock-in-duced analgesia: Antagonism by nal­oxone is possible only before induction of analgesia. Brain Res 242:309-316, 1982

149. Watkins LR, Mayer DJ: Organization of endogenous opiate and nonopiate pain control systems. Science 216:1185-1192,1982

150. Watkins LR, Young EG, Kinscheck IB, et al: The neural basis of footshock analgesia: The role of specific ventral medullary nuclei. Brain Res 276:305-315, 1983

151. Weil-Fugazza J, Godefroy F, Coudert D, et al: Morphine analgesia and newly synthesized 5-hydroxytryptamine in the dorsal and the ventral halves of the spinal cord of the rat. Brain Res 214:440-444, 1981

152. Willis WD, Gerhart KD, Willcockson WS, et al: Primate raphe- and reticulo­spinal neurons effects of stimulation in periaqueductal gray or VPL thalamic nucleus. J Neurophysiol 51:467-480, 1984

153. Willis WD, Kevetter GA: Spinothalamic cells in the rat lumbar cord with collat­erals to the medullary reticular forma­tion. Brain Res 238:181-185, 1982

154. Willis WD, Kenshalo DR, Leonard RB, et al: Facilitation of the responses of primate spinothalamic cells to cold and to tactile stimuli by noxious heating of the skin. Pain 12:141-152, 1982

155. Wong CL, Bentley GA: The effect of stress and adrenalectomy on morphine analgesia and naloxone potency in mice. Eur J Pharmacol 56:197-205, 1979

156. Woolf CJ, Wall PD: Chronic peripheral nerve section diminishes the primary afferent A-fibre mediated inhibition of rat dorsal horn neurones. Brain Res 242:77-85, 1982

157. Yezierski RP, Gerhart KD, Schrock BJ, et al: A further examination of effects of cortical stimulation on primate spi­nothalamic tract cells. J Neurophysiol 49:424-441, 1983

158. Yokota T: Differential inhibitory effects of volleys from dorsal raphe nucleus upon spinal and spino-bulbo-spinal re­flexes. Neurosci Lett 7:291-294, 1978

159. Young EG, Watkins LR, Mayer DJ: Comparison of the effects of ventral medullary lesions on systemic and mi­croinjection morphine analgesia. Brain Res 290:119-129, 1984

160. Zamir N, Shuber E: Altered pain per­ception in hypertensive humans. Brain Res 201:471-474, 1980

161. Zamir N, Simantov R, Segal M: Pain sensitivity and opioid activity in geneti­cally and experimentally hypertensive rats. Brain Res 184:299-310, 1980

162. Zieglgansberger W, Tulloch IF: The ef­fects of methionine- and leucine-en­kephalin on spinal neurones of the cat. Brain Res 167:53-64, 1979

163. Zorman G, Hentall ID, Adams JE, et al: Naloxone-reversible analgesia pro­duced by microstimulation in the rat medulla. Brain Res 219:137-148, 1981

PAIN: GENERAL CLINICAL-SURGICAL APPROACHES

1. Amodei N, Paxinos G: Unilateral knife cuts produce ipsilateral suppression of responsiveness to pain in the formalin test. Brain Res 193:85-94, 1980

2. Aronoff GM, Evans WO, Enders PL: A review of follow-up studies of multidisci-plinary pain units. Pain 16:1-11, 1983

3. Badawy AA-B, Evans M, Punjani NF, et al: Does naloxone always act as an opiate antagonist? Life Sci 33:739-742, 1983

4. Carlen PL, Wall PD, Nadvorna H, et al: Phantom limbs and related phenomena in recent traumatic amputation. Neurol­ogy 28:211-217, 1978

5. Carstens E, Guinan MJ, MacKinnon JD: Naloxone does not consistently affect inhibition of spinal nociceptive transmis­sion produced by medial diencephalic stimulation in the cat. Neurosci Lett 42:71-76, 1983

6. Chayen MS, Rudick V, Borvine A: Pain control with epidural injection of mor­phine. Anesthesiology 53:338-339, 1980

7. Cohen FL: Postsurgical pain relief: Pa­tients' status and nurses' medication choices. Pain 9:265-274, 1980

8. Croze S, Duclaux R: Thermal pain in humans: Influence of the rate of stimu­lation. Brain Res 157:418-421, 1978

9. Devor M: Nerve pathophysiology and mechanisms of pain in causalgia. J Auton Nerv Syst 7:371-384, 1983

10. File SE: Naloxone reduces social and exploratory activity in the rat. Psycho-pharmacology (Berlin) 71:41-44, 1980

11. Gracely RH, Dubner R: Pain assessment in humans—a reply to Hall. Pain 11:109-120, 1981

12. Holden C: Pain, dying, and the health care system. Science 203:984-986, 1979

13. Jacquet YF: Different behavioral effects following intracerebral, intracerebroven-tricular or intraperitoneal injections of naloxone in the rat. Behav Brain Res 1:543-546, 1980

14. Kenton B, Coger R, Crue B, et al: Pe­ripheral fiber correlates to noxious ther­mal stimulation in humans. Neurosci Lett 17:301-306, 1980

15. MacDonald AJR: Abnormally tender muscle regions and associated painful movements. Pain 8:197-205, 1980

16. Maruyama Y, Shimoji K, Shimizu H, et al: Effects of morphine on human spinal cord and peripheral nervous activities. Pain 8:63-73, 1980

17. Nashold BS, Ostdahl RH: Dorsal root entry zone lesions for pain relief. J Neu-rosurg 51:59-69, 1979

18. Sherman RA, Sherman CJ, Gall NG: A survey of current phantom limb pain treatment in the United States. Pain 8:85-99, 1980

19. Strassburg HM, Thoden U, Mundinger F: Mesencephalic chronic electrodes in pain patients. Appl Neurophysiol 42:284-293, 1979

20. Varni JW, Gilbert A, Dietrich SL: Behav­ioral medicine in pain and analgesia in management for the hemophilic child with factor VIII inhibitor. Pain 11:121-126, 1981

21. Wahlstrom A, Terenius L: Factor in hu­man CSF with apparent morphine-antag­onistic properties. Acta Physiol Scand 110:427-429, 1980

22. Walker JM, Moises HC, Coy DH, et al: Nonopiate effects of dynorphin and des-tyr-dynorphin. Science 218:1136-1138, 1982

23. Watson SJ, Khachaturian H, Akil H, et al: Comparison of the distribution of dy­norphin systems and enkephalin sys-

328 PHYSICAL THERAPY

PRACTICE

terns in brain. Science 218:1134-1136, 1982

24. Wilier JC, Bussel B: Evidence for a direct spinal mechanism in morphine-induced inhibition of nociceptive reflexes in hu­mans. Brain Res 187:212-215, 1980

PAIN: ACUPUNCTURE

1. Bragin EO, Vasilenko GF, Durinjan RA: The study of the central grey matter in mechanisms of different kinds of anal­gesia: Effects of lesions. Pain 16:33-40, 1983

2. Brattberg G: Acupuncture therapy for tennis elbow. Pain 16:285-288, 1983

3. Chapman CR, Colpitts YM, Benedetti C, et al: Evoked potential assessment of acupunctural analgesia: Attempted re­versal with naloxone. Pain 9:183-197, 1980

4. Chapman CR, Sato T, Martin RW, et al: Comparative effects of acupuncture in Japan and the United States on dental pain perception. Pain 12:319-328, 1982

5. Cheng RSS, Pomeranz BH: Electroacu-puncture analgesia could be mediated by at least two pain-relieving mecha­nisms: Endorphin and non-endorphin systems. Life Sci 25:1957-1962, 1979

6. Cheng RSS, Pomeranz BH: Electroacu-puncture analgesia is mediated by ster-eospecific opiate receptors and is re­versed by antagonists of type I recep­tors. Life Sci 26:631-638, 1980

7. Cheng RSS, Pomeranz BH: Monoami-nergic mechanism of electroacupuncture analgesia. Brain Res 215:77-92, 1981

8. Cheng RSS, Pomeranz BH, Yu G: Elec­troacupuncture treatment of morphine-dependent mice reduces signs of with­drawal, without showing cross-toler­ance. Eur J Pharmacol 68:477-481, 1980

9. Crosby WH, Ulett GA: Acupuncture treatments for pain relief. JAMA 245:768-769, 1981

10. Dimitrijevic MR, Faganel J, Young RR: Underlying mechanisms of the effect of spinal cord stimulation in motor disor­ders. Appl Neurophysiol 44:133-140, 1981

11. Epler DC: Bloodletting in early Chinese medicine and its relation to the origin of acupuncture. Bull Hist Med 54:337-367, 1980

12. Eriksson MBE, Sjolund BH, Nielzen S: Long term results of peripheral condition­ing stimulation as an analgesic measure in chronic pain. Pain 6:335-347, 1979

13. Facchinetti F, Nappi G, Savoldi F, et al: Primary headaches: Reduced circulating beta-lipotropin and beta-endorphin levels with impaired reactivity to acupuncture. Cephalalgia 1:195-201, 1981

14. Fu T-C, Halenda SP, Dewey WL: The effect of hypophysectomy on acupunc­ture analgesia in the mouse. Brain Res 202:33-39, 1980

15. Gwei-Djen L, Needham J: A scientific basis for acupuncture? The Sciences 19:1-10,1979

16. Ha H, Tan E-C, Fukunaga H, et al: Nal­oxone reversal of acupuncture analgesia in the monkey. Exp Neurol 73:298-303, 1981

17. Ha H, Wu RS, Contreras RA, et al: Meas­urement of pain threshold stimulation of tooth pulp afferents in the monkey. Exp Neurol 61:260-269, 1978

18. Handelmann GF, Quirion R: Neonatal ex­posure to morphine increases micro-op­iate binding in the adult forebrain. Eur J Pharmacol 94:357-358, 1983

19. Higby D: The nature of pain in patients with cancer—a summary. J Med 13:253-255, 1982

20. Ho WKK, Wen HL, Lam S, et al: The influence of electro-acupuncture on nal-oxone-induced morphine withdrawal in mice: Elevation of brain opiate-like activ­ity. Eur J Pharmacol 49:197-199, 1978

21. Homma I, Motomiya Y: The inhibitory effect of acupuncture on the tonic vibra­tion reflex (TVR) in man. Neurosci Lett 28:315-318, 1982

22. Homma S, Homma I: Inhibitory effect of acupuncture of the vibration-induced grasp reflex in man. Neurosci Lett 32:209-212, 1982

23. Iriki A: Site and action of electroacu-puncture-induced effects on the rat jaw-opening reflex. Exp Neurol 75:36-50, 1982

24. Iriki A, Toda K: Morphine and electroac­upuncture: Comparison of the effects on the cortical evoked responses after tooth pulp stimulation in rats. Eur J Pharmacol 68:83-87, 1980

25. Ishiko N, Yamamoto T, Murayama N, et al: Electroacupuncture: Current strength-duration relationship for initia­tion of hypesthesia in man. Neurosci Lett 8:273-276, 1978

26. Kawakita K: Role of the polymodal re­ceptors in acupuncture analgesia of the rat. Comparative Medicine East and West 6:312-321, 1982

27. Kawakita K, Funakoshi M: Suppression of the jaw-opening reflex by conditioning A-delta fiber stimulation and electroacu­puncture in the rat. Exp Neurol 78:461-465, 1982

28. Kerr FWL, Wilson PR, Nijensohn DE: Acupuncture reduces the trigeminal evoked response in decerebrate cats. Exp Neurol 61:84-95, 1978

29. Kline RL, Yeung KY, Calaresu FR: Role of somatic nerves in the cardiovascular responses to stimulation of an acupunc­ture point in anesthetized rabbits. Exp Neurol 61:561-570, 1978

30. Lamontagne Y, Annable L, Gagnon M-A: Acupuncture for smokers: Lack of long-term therapeutic effect in a con­trolled study. Can Med Assoc J 122:787-790, 1980

31. Lee MHM, Zaretsky HH, McMeniman M: Acupuncture analgesia-assessment us­ing electric tooth-pulp stimulation: Pre­liminary report. NY State J Med 78:1687-1690, 1978

32. Lewit K: The needle effect in the relief of myofascial pain. Pain 6:83-90, 1979

33. Lewith GT, Field J, Machin D: Acupunc­ture compared with placebo in post-her-petic pain. Pain 17:361-368, 1983

34. Lewith GT, Machin D: On the evaluation of the clinical effects of acupuncture. Pain 16:111-127, 1983

35. Lu G-W: Characteristics of afferent fiber innervation on acupuncture points zu-sanli. Am J Physiol 345:606-612, 1983

36. Mao W, Ghia JN, Scott DS, et al: High versus low intensity acupuncture anal­gesia for treatment of chronic pain: Ef­fects on platelet serotonin. Pain 8:331-342, 1980

37. Melzack R, Katz J: Ariculotherapy fails to relieve chronic pain: A controlled crossover study. JAMA 251:1041 -1043, 1984

38. Monga TN, Jaksic T: Acupuncture in phantom limb pain. Arch Phys Med Re-habil 62:229-231,1981

39. Nappi G, Facchinette F, Bono G, et al: Plasma opioid levels in post-traumatic chronic headache and trigeminal neural­gia: Maintained response to acupunc­ture. Headache 22:276-279, 1982

40. Nappi G, Facchinetti F, Legnante G, et al: Different releasing effects of tradi­tional manual acupuncture and elec­troacupuncture on proopiocortin-related peptides. Acupunct Electrother Res 7:93-103, 1982

41. Oleson TD, Kroening RJ, Bresler DE: An experimental evaluation of auricular di­agnosis: The somatotopic mapping of musculoskeletal pain at ear acupuncture sets. Pain 8:217-229, 1980

42. Pomeranz B: Do endorphins mediate acupuncture analgesia? In Costa E, Tra-bucci M (eds): Advances in Biochemical Psychopharmacology, New York, NY, Raven Press, 1978, vol 18, pp 351-359

43. Pomeranz B, Paley D: Electroacupunc­ture hypalgesia is mediated by afferent nerve impulses: An electrophysiological study in mice. Exp Neurol 66:398-402, 1979

44. Pullan PT, Finch PM, Yuen RWM, et al: Endogenous opiates modulate release of growth hormone in response to elec­troacupuncture. Life Sci 32:1705-1709, 1983

45. Reshetnyak VK, Meizerov EE, Durinyan RA: Changes in functional activity of the large hemispheric cortex and central gray matter in response to electroacu­puncture. Research findings from the Central Research Institute of Reflexo-therapy, Moscow, 1982

46. Rico RC, Hobika GH, Avellanosa AM, et al: Use of intrathecal and epidural mor­phine for pain relief in patients with ma­lignant diseases: A preliminary report. J Med 13:223-231, 1982

47. Rico RC, Trudnowski RJ: Studies with electro-acupuncture. J Med 13:247-251,1982

48. Riscalla LM: Toward establishing scien­tific credibility in acupuncture research. Med Hypotheses 5:221-224, 1979

49. Sandrew BB, Yang RCC, Wang SC: Electro-acupuncture analgesia in mon­keys: A behavioral and neurophysiologi-cal assessment. Arch Int Pharmacodyn Ther 231:274-284, 1978

50. Sarnat HB, Morrissy RT: Idiopathic tor­ticollis: Sternocleidomastoid myopathy and accessory neuropathy. Muscle Nerve 4:374-380, 1981

Volume 65 / Number 3, March 1985 329

PRACTICE

51. Shiner G: Relief from chronic pain: Stim­ulating the "Morphine Within." Research Resources Reporter 5:1-5, 1981

52. Sodipo JOA: Therapeutic acupuncture for chronic pain. Pain 7:359-365, 1979

53. Toda K: Effects of electro-acupuncture on rat jaw opening reflex elicited by tooth pulp stimulation. Jpn J Physiol 28:485-497, 1978

54. Toda K, Atsushi I, Tanaka H: Electroac-upuncture suppresses the cortical evoked responses in somatosensory I and II areas after tooth pulp stimulation in rat. Jpn J Physiol 30:487-490, 1980

55. Toda K, Ichioka M: Afferent nerve infor­mation underlying the effects of elec-troacupuncture in rat. Exp Neurol 65:457-561, 1979

56. Toda K, Ichioka M, Iriki A, et al: Elec-troacupuncture effects on the field po­tentials in the caudal part of the spinal trigeminal nucleus evoked by tooth pulp stimulation in rat. Exp Neurol 64:704-709, 1979

57. Toda K, Iriki A: Effects of electroacu-puncture on thalamic evoked responses recorded from the ventrobasal complex and posterior nuclear group after tooth pulp stimulation in rat. Exp Neurol 66:419-422, 1979

58. Trudnowski RJ: Current concepts in pro­viding pain relief for cancer patients: In­troductory remarks. J Med 13:145, 1982

59. Zhang A, Pan X, Xu S, et al: Endorphins and acupuncture analgesia. Chin Med J [Engl] 93:673-680, 1980

PAIN: NEUROPHARMACOLOGICAL

A. Endogenous Opiates (enkephalins)—Human

1. Akil H, Watson SJ, Sullivan S, et al: Enkephalin-like material in normal human CSF: Measurement and levels. Life Sci 23:121-126, 1978

2. Almay BGL, Johansson F, Von Knorring L, et al: Endorphins in chronic pain. I. Differences in CSF endorphin levels be­tween organic and psychogenic pain syndromes. Pain 5:153-162, 1978

3. Amano K, Kitamura K, Kawamura H, et al: Alterations of immunoreactive beta-endorphin in the third ventricular fluid in response to electrical stimulation of the human periaqueductal gray matter. Appl Neurophysiol 43:150-158, 1980

4. Bjorndal N, Casey DE, Gerfach J: En­kephalin, morphine and naloxone in tar­dive dyskinesia. Psychopharmacology 69:133-136, 1980

5. Budd K: Psychotropic drugs in the treat­ment of chronic pain. Anaesthesia 33:531-534, 1978

6. Carr DB, Bullen BA, Skrinar GS, et al: Physical conditioning facilitates the ex­ercise-induced secretion of beta-endor-phin and beta-lipotropin in women. N Engl J Med 305:560-563, 1981

7. Chery-Croze S, Duclaux R: Discrimina­tion of painful stimuli in human beings: Influence of stimulation area. J Neuro­physiol 44:1-10, 1980

8. Chou J, Tang J, Costa E: MET5-Enkeph-alin-ARG6-PHE7 content of human and rabbit plasma. Life Sci 32:2589-2595, 1983

9. Czlonkowski A, Costa T, Przewlocki R, et al: Opiate receptor binding sites in human spinal cord. Brain Res 267:392-396, 1983

10. deLanerolle NC, Lamotte CC: The hu­man spinal cord: Substance P and me­thionine-enkephalin immunoreactivity. J Neurosci 2:1369-1386, 1982

11. Fessler RG, Brown FD, Rachlin JR, et al: Elevated Beta-endorphin in cerebro­spinal fluid after electrical brain stimula­tion: Artifact of contrast infusion? Sci­ence 224:1017-1018, 1984

12. Foley KM, Kourides IA, Inturrisi CE, et al: Beta-endorphin: Analgesic and hor­monal effects in humans. Proc Natl Acad Sci USA 76:5377-5381, 1979

13. Furui T, Kageyama N, Kuwayama A, et al: Increase of beta-endorphin in cerebro­spinal fluid after removal of ACTH-se-creting pituitary adenomas. Pain 11:127-132, 1981

14. Furui T, Kageyama N, Haga T, et al: Radioreceptor assay of methionine-en-kephalin-like substance in human cere­brospinal fluid. Pain 9:63-72, 1980

15. Gerner RH, Sharp B: CSF beta-endor-phin-immunoreactivity in normal, schizo­phrenic, depressed, manic and anorexic subjects. Brain Res 237:244-247, 1982

16. Gintzler AR: Endorphin-mediated in­creases in pain threshold during preg­nancy. Science 210:193-195, 1980

17. Gramsch C, Hollt V, Mehraein P, et al: Regional distribution of methionine-en­kephalin- and beta-endorphin-like immu­noreactivity in human brain and pituitary. Brain Res 171:261-270, 1979

18. Grevert P, Albert LH, Goldstein A: Partial antagonism of placebo analgesia by nal­oxone. Pain 16:129-143, 1983

19. Hollt V, Muller OA, Fahlbusch R: Beta-endorphin in human plasma: Basal and pathologically elevated levels. Life Sci 25:27-44, 1979

20. Hosobuchi Y, Lamb S, Baskin D: Tryp­tophan loading may reverse tolerance to opiate analgesics in humans: A prelimi­nary report. Pain 9:161-169, 1980

21. Houck JC, Kimball C, Chang C, et al: Placental beta-endorphin-like peptides. Science 207:78-80, 1980

22. Kaiya H, Tanaka T, Takeuchi K, et al: Decreased level of beta endorphin-like immunoreactivity in cerebrospinal fluid of patients with senile dementia of Alz­heimer type. Life Sci 33:1039-1043, 1983

23. LaMotte CC, deLanerolle NC: Human spinal neurons: Innervation by both sub­stance P and enkephalin. Neuroscience 6:713-723, 1981

24. Levine JD, Gordon NC, Smith R, et al: Analgesic responses to morphine and placebo in individuals with postoperative pain. Pain 10:379-389, 1981

25. Lewis JW, Tordoff MG, Sherman JE, et al: Adrenal medullary enkephalin-like peptides may mediate opioid stress an­algesia. Science 217:557-559, 1982

26. McCain HW, Lamster IB, Bozzone JM, et al: B-Endorphin modulates human im­mune activity via non-opiate receptor mechanisms. Life Sci 31:1619-1624, 1982

27. Naber D, Pickar D, Dionne RA, et al: Assay of endogenous opiate receptor ligands in human CSF and plasma. Subst Alcohol Actions Misuse 1:83-91, 1980

28. Nicoll RA, Alger BE, Jahr CE: Peptides as putative excitatory neurotransmitters: Carnosine, enkephalin, substance P and TRH. Proc R Soc Lond [Biol] 210:1333-1340, 1980

29. Nyberg F, Wahlstrom A, Sjolund B, et al: Characterization of electrophoretically separable endorphins in human CSF. Brain Res 259:267-274, 1983

30. Piercey MF, Schroeder LA: Spinal and supraspinal sites for morphine and ne­fopam analgesia in the mouse. Eur J Pharmacol 74:135-140, 1981

31. Piercey MF, Varner K, Schroeder LA: Analgesic activity of intraspinally admin­istered dynorphin and ethylketocyclazo-cine. Eur J Pharmacol 80:283-284, 1982

32. Pique L, Bertagna X, Javoy-Agid F, et al: Simultaneous measurement of beta-endorphin and y-lipotropin-like peptides in the human hypothalamus. Neuropep­tides 2:99-108, 1981

33. Quails PJ, Sheehan PW: Electromy-ograph biofeedback as a relaxation tech­nique: A critical appraisal and reassess­ment. Psychol Bull 90:21-42, 1981

34. Richardson DE: Analgesia produced by stimulation of various sites in the human beta-endorphin system. Appl Neuro­physiol 45:116-122, 1982

35. Rossier J, Bloom FE, Guillemin R: Stim­ulation of human periaqueductal gray for pain relief increases immunoreactive beta-endorphin in ventricular fluid. Sci­ence 203:279-281, 1979

36. Sana A, Wilson SP, Molnar A, et al: Substance P and opiate-like peptides in human adrenal medulla. Neurosci Lett 20:195-200, 1980

37. Sarne Y, Azov R, Weissman BA: A sta­ble enkephalin-like immunoreactive sub­stance in human CSF. Brain Res 151:399-403, 1978

38. Sarne Y, Gil-Ad I, Laron Z: Regulation of hypophysial secretion by endogenous opiates: Humoral endorphin stimulates the release of growth hormone. Life Sci 28:681-686, 1981

39. Same Y, Weissman BA, Keren O, et al: Humoral endorphin: A new endogenous factor with opiate-like activity. Life Sci 28:673-680, 1981

40. Scott DS: Treatment of the myofascial pain-dysfunction syndrome: Psychologi­cal aspects. J Am Dent Assoc 101:611 -616, 1980

41. Stacher G, Bauer P, Steinringer H, et al: Effects of the synthetic enkephalin ana­logue FK 33-824 on pain threshold and pain tolerance in man. Pain 7:159-172, 1979

42. Steinbrook RA, Carr DB, Datta S, et al: Dissociation of plasma and cerebrospinal fluid beta-endorphin-like immunoactivity levels during pregnancy and parturition. Anesth Analg 61:893-897, 1982

330 PHYSICAL THERAPY

PRACTICE

43. Suda T, Liotta AS, Krieger DT: Beta-Endorphin is not detectable in plasma from normal human subjects. Science 202:221-223, 1978

44. Tamsen A, Sukurada T, Wahlstrom A, et al: Postoperative demand for analge­sics in relation to individual levels of en­dorphin and substance P in cerebrospi­nal fluid. Pain 13:171-183, 1982

45. Taquet H, Javoy-Agid F, Hamon M, et al: Parkinson's disease affects differently met- and leu-enkephalin in the human brain. Brain Res 280:379-382, 1983

46. Volavka J, Bauman J, Pevnick J, et al: Short-term hormone effects of naloxone in man. Psychoneuroendocrinology 5: 225-234, 1980

47. Von Knorring L, Almay BGL, Johansson F, et al: Circannual variation in concen­trations of endorphins in cerebrospinal fluid. Pain 12:265-272, 1982

48. Von Knorring L, Almay BGL, Johansson F, et al: Endorphins in CSF of chronic pain patients, in relation to augmenting-reducing response in visual averaged evoked response. Neuropsychobiology 5:322-326, 1979

49. Von Knorring L, Almay BGL, Johansson F, et al: Pain perception and endorphin levels in cerebrospinal fluid. Pain 5:359-365, 1978

50. Wilier JC, Albe-Fessard D: Electrophys­iological evidence for a release of endog­enous opiates in stress-induced analge­sia in man. Brain Res 198:419-426, 1980

51. Yaksh TL, Elde RP: Release of methio­nine-enkephalin immunoreactivity from the rat spinal cord in vivo. Eur J Phar­macol 63:359-362, 1980

PAIN: NEUROPHARMACOLOGICAL

B. Endogenous Opiates (enkephalins)—Animal

1. Adler MW: The in vivo differentiation of opiate receptors: Introduction. Life Sci 28:1543-1545, 1981

2. Alleva E, Castellano C, Oliverio A: Ef­fects of L- and D-amino acids on anal­gesia and locomotor activity of mice: Their interaction with morphine. Brain Res 198:249-252, 1980

3. Antelman SM, Rowland N: Endoge­nous opiates and stress-induced eat­ing. Science 214:1149, 1981

4. Armitage SE, Baldwin BA, Vince MA: Opiate receptor function may be mod­ulated through an oxidation-reduction mechanism. Science 208:1171-1174, 1980

5. Aronin N, DiFiglia M, Liotta AS, et al: Ultrastructural localization and bio­chemical features of immunoreactive leu-enkephalin in monkey dorsal horn. J Neurosci 1:561-577, 1981

6. Audigier Y, Mazarguil H, Gout R, et al: Structure-activity relationships of en­kephalin analogs at opiate and enkeph­alin receptors: Correlation with analge­sia. Eur J Pharmacol 63:35-46, 1980

7. Azami J, Llewelyn MB, Roberts MHT: Antagonism of the analgesic effects of

systemically administered morphine by injection of naloxone intracerebrally and lesions of nucleus raphe magnus. J Physiol (Lond) 306:16-17, 1979

8. Azami J, Llewelyn MB, Roberts MHT: The analgesic effects of morphine mi-croinjected into nucleus reticularis par-agigantocellularis—comparison with nucleus raphe magnus and the effects of nucleus raphe magnus lesions. J Physiol (Lond) 306:17-18, 1979

9. Barker JL, Neale JH, Smith TG Jr, et al: Opiate peptide modulation of amino acid responses suggests novel form of neuronal communication. Science 199:1451-1453, 1978

10. Barker JL, Smith TG Jr, Neale JH: Mul­tiple membrane actions of enkephalin revealed using cultured spinal neurons. Brain Res 154:153-158, 1978

11. Barrett RW, Vaught JL: The effects of receptor selective opioid peptides on morphine-induced analgesia. Eur J Pharmacol 80:427-430, 1982

12. Beitz AJ: The sites of origin of brain stem neurotensin and serotonin projec­tions to the rodent nucleus raphe mag­nus. J Neurosci 2:829-842, 1982

13. Billet M, Elghozi JL, Meyer P, et al: Central cardiovascular effects on nar­cotic analgesics and enkephalins in rats. Br J Pharmacol 71:365-369, 1980

14. Bloom F, Battenberg E, Rossier J, et al: Neurons containing beta-endorphin in rat brain exist separately from those containing enkephalin: Immunocyto-chemical studies. Proc Natl Acad Sci USA 75:1591-1595, 1978

15. Blum K, Briggs AH, Elston SFA, et al: Reduced leucine-enkephalin-like im­munoreactive substance in hamster basal ganglia after long-term ethanol exposure. Science 216:1425-1426, 1982

16. Botticelli LJ, Wurtman RJ: Septohip-pocampal cholinergic neurons are reg­ulated trans-synaptically by endorphin and corticotropin neuropeptides. J Neurosci 2:1316-1321, 1982

17. Carr DB, Bergland R, Hamilton A, et al: Endotoxin-stimulated opioid peptide secretion: Two secretory pools and feedback control in vivo. Science 217:845-848, 1982

18. Cesselin F, Oliveras JL, Bourgoin S, et al: Increased levels of met-enkephalin-like material in the CSF of anaesthe­tized cats after tooth pulp stimulation. Brain Res 237:325-338, 1982

19. Clark WG, Bemardini GL: Beta-endor-phin-induced hyperthermia in the cat. Peptides (Fayetteville) 2:371-373, 1981

20. Clark WG: Effects of opioid peptides on thermoregulation. Fed Proc 40: 2754-2759, 1981

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48. Jacquet YF: Opiate effects after adren-ocorticotrophin or beta-endorphin in­jection in the periaqueductal gray mat­ter of rats. Science 201:1032-1034, 1978

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332 PHYSICAL THERAPY

PRACTICE

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PAIN: NEUROPHARMACOLOGICAL

C. Serotonergic Mechanisms 1. Aiello-Malmberg P, Bartolini A, Bartolina

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PAIN: NEUROPHARMACOLOGICAL

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43. White JM, Holtzman SG: The effects of naloxone, diprenorphine, and diazepam on responding suppressed by pre-shock and pre-food stimuli. Life Sci 32:479-486, 1982

334 PHYSICAL THERAPY

PRACTICE

44. Wilson PR, Yaksh TL: Baclofen is anti­nociceptive in the spinal intrathecal space of animals. Eur J Pharmacol 51:323-330, 1978

45. Yaksh TL, Howe JR: Opiate receptors and their definition by antagonists. Anes­thesiology 56:246-249, 1982

46. Yeung JC, Rudy TA: Multiplicative inter­action between narcotic agonisms ex­pressed at spinal and supraspinal sites of antinociceptive action as revealed by concurrent intrathecal and intracerebro-ventricular injections of morphine. J Pharmacol Exp Ther 215:633-642, 1980

47. Yeung JC, Rudy TA: Sites of antinoci­ceptive action of systemically injected morphine: Involvement of supraspinal loci as revealed by intracerebroventricu-lar injection of naloxone. J Pharmacol Exp Ther 215:626-632, 1980

48. Young AM, Woods JH: Limitations on the antagonistic actions of opioid antag­onists. Federation Proc 41:2333-2338, 1982

PAIN: NEUROPHARMACOLOGICAL

E. Neurotransmitters, Morphine, and Other Drugs

1. Amir S: Effects of ACTH on pain respon­siveness in mice: Interaction with mor­phine. Neuropharmacology 20:959-962, 1981

2. Auguy-Valette A, Cros J, Gouarderes C, et al: Morphine analgesia and cerebral opiate receptors: A developmental study. Br J Pharmacol 63:303-308, 1978

3. Baraban JM, Wang RY, Aghajanian GK: Reserpine suppression of dorsal raphe neuronal firing: Mediation by adrenergic system. Eur J Pharmacol 52:27-36, 1978

4. Berge O-G, Hole K: Tolerance to the antinociceptive effect of morphine in the spinal rat. Neuropharmacology 20:653-657,1981

5. Chan SHH: Participation of the nucleus reticularis gigantocellularis in the mor­phine suppression of jaw-opening reflex in cats. Brain Res 160:277-280, 1979

6. Clark WG, Bemardini GL: Morphine-in­duced hyperthermia: Lack of cross-tol­erance with enkephalin analogs. Brain Res 231:231-234, 1982

7. Cohn ML, Cohn M, Taylor FH: Guano-sine 3', 5'-monophosphate: A central nervous system regulator of analgesia. Science 199:319-322, 1978

8. Collins JG, Bock J, Homma E, et al: Serum morphine levels in cats during dorsal horn neuron suppression by spin-ally administered morphine. Life Sci 31:2145-2148, 1982

9. Dafny N, Burks TF: Selective modifica­tion by opiates of neuronal activity of the medial basal hypothalamus. Exp Neurol 72:1-11,1981

10. Davies J, Dray A: Depression and facili­tation of synaptic responses in cat dorsal horn by substance P administered into substantia gelatinosa. Life Sci 27:2037-2042, 1980

11. Delander GE, Takemori AE: Spinal an­tagonism of tolerance and dependence induced by systemically administered morphine. Eur J Pharmacol 94:35-42, 1983

12. Doi T, Jurna I: Intrathecal substance P depresses spinal motor and sensory re­sponses to spina® stimulation of nocicep­tive afferents—antagonism by naloxone. Naunyn Schmiedebergs Arch Pharmacol 319:154-160, 1982

13. Einsppahr FJ, Piercey MF: Morphine de­presses dorsal horn neuron responses to controlled noxious and non-noxious cutaneous stimulation. J Pharmacol Exp Ther 213:456-461, 1980

14. Frederickson RCA, Burgiss V, Harrell CE, et al: Dual actions of substance P on nociception: Possible role of endoge­nous opioids. Science 199:1359-1362, 1978

15. Frenk H, Liban A, Balamuth R, et al: Opiate and non-opiate aspects of mor­phine induced seizures. Brain Res 253:253-261, 1982

16. Gebhert GF, Sandkuhler J, Thalhammer JG, et al: Inhibition in spinal cord of no­ciceptive information by electrical stimu­lation and morphine microinjection at identical sites in midbrain of the cat. J Neurophysiol 51:75-89, 1984

17. Haigler HJ, Spring DD: Substance P, morphine and methionine-enkephalin: Ef­fects on spontaneous and evoked neu­ronal firing in the nucleus reticularis gi­gantocellularis of the rat. Eur J Pharma­col 67:65-74, 1980

18. Hammond DL, Levy RA, Proudfit HK: Hypoalgesia following microinjection of noradrenergic antagonists in the nucleus raphe magnus. Pain 9:85-101, 1980

19. Henderson G, Hughes J, Kosterlitz HW: In vitro release of leu- and met-enkeph-alin from the corpus striatum. Nature 271:677-679, 1982

20. Hosford DA, Haigler HJ: Morphine and methionine-enkephalin: Different effects on spontaneous and evoked neuronal firing in the mesencephalic reticular for­mation of the rat. J Pharmacol Exp Ther 213:355-363, 1980

21. Iversen LL, Iversen SD, Bloom FE, et al: Release of enkephalin from rat globus pallidus in vitro. Nature 271:679-681, 1978

22. Joyce EM, Iversen SD: The effect of morphine applied locally to mesence­phalic dopamine cell bodies on sponta­neous motor activity in the rat. Neurosci Lett 14:207-212, 1979

23. Jurna I: Aminophyline differentiates be­tween the depressant effects of mor­phine on the spinal nociceptive reflex and on the spinal ascending activity evoked from afferent C fibres. Eur J Pharmacol 71:393-400,1981

24. Jurna I, Heinz G, Blinn G, et al: The effect of substantia nigra stimulation and mor­phine on A-motoneurones and the tail-flick response. Eur J Pharmacol 51:239-250,1978

25. Jurna I, Zetler G: Antinociceptive effect of centrally administered caerulein and cholecystokinin octapeptide (CCK-8). Eur J Pharmacol 73:323-331, 1981

26. Klemm WR, Mallari CG: Effects of mor­phine and naloxone on the responsive­ness (unit and field potential) of three opiate-relevant brain areas during elec­trical stimulation of the substantia nigra. Prog Neuropsychopharmacol Biol Psy­chiatry 4:1-12, 1980

27. Konishi S, Tsunoo A, Otsuka M: En­kephalins presynaptically inhibit cholin­ergic transmission in sympathetic gan­glia. Nature 383:515-516,1979

28. Konishi S, Tsunoo A, Otsuka M: Sub­stance P and noncholinergic excitatory synaptic transmission in guinea pig sym­pathetic ganglia. Proceedings of the Ja­pan Academy 55:525-530, 1979

29. Kostowski W, Jerlicz M, Bidzinski A, et al: Reduced analgesic effects of mor­phine after bilateral lesions of the locus coeruleus in rats. Pol J Pharmacol Pharm 39:49-53,1978

30. Kuriyama K, Yoneda Y: Morphine in­duced alterations of y-aminobutyric acid and taurine contents and L-glutamate decarboxylase activity in rat spinal cord and thalamus: Possible correlates with analgesic action of morphine. Brain Res 148:163-179, 1978

31. Levy RA, Proudfit HK: Analgesia pro­duced by microinjection of baclofen and morphine at brain stem sites. Eur J Phar­macol 57:43-55, 1979

32. Lewis JW, Sherman JE, Liebeskind JC: Opioid and non-opioid stress analgesia: Assessment of tolerance and cross-tol­erance with morphine. J Neurosci 1:358-363,1981

33. Lineberry CG, Kulics AT: The effects of diazepam, morphine and lidocaine on no­ciception in rhesus monkeys: A signal detection analysis. J Pharmacol Exp Ther 205:302-310, 1978

34. Lorez HP, Kemali M: Substance P-, met-enkephalin-and somatostatin-like immu-noreactivity distribution in the frog spinal cord. Neurosci Lett 26:119-124, 1981

35. Murase K, Nedeljkov V, Randic M: The actions of neuropeptides on dorsal horn neurons in the rat spinal cord slice prep­aration: An intracellular study. Brain Res 234:170-176, 1982

36. Palmer MR, Klemm WR: Adrenergic al­teration of morphine-induced suppres­sion of sciatic-evoked unit responses in the central grey. Progress in Neuro-Psy-chopharmacology 2:337-347, 1978

37. Piercey MF, Dorbry PJK, Schroeder LA, et al: Behavioral evidence that substance P may be a spinal cord sensory neuro­transmitter. Brain Res 210:407-412, 1981

38. Pomeroy SL, Behbehani MM: Response of nucleus raphe magnus neurons to iontophoretically applied substance P in rats. Brain Res 202:464-468, 1980

39. Proudfit HK, Levy RA: Delimitation of neuronal substrates necessary for the analgesic action of baclofen and mor­phine. Eur J Pharmacol 47:159-166, 1978

40. Randic M, Carstens E, Zimmermann M, et al: Dual effects of substance P on the excitability of single cutaneous primary afferent C- and A-fibers in the cat spinal cord. Brain Res 233:389-393,1982

Volume 65 / Number 3, March 1985 335

41. Schwartz AS, Woolf B, Hedin C, et al: Dissociation of discrimination of skin warming from skin cooling by morphine in monkeys. Brain Res 156:206-210, 1978

42. Slater P, Blundell C: The effects of a permanent and selective depletion of brain catecholamines on the antinocicep­tive action of morphine. Arch Pharm (Weinheim) 305:337-343, 1978

43. Snyder SH: Brain peptides as neuro­transmitters. Science 209:976-983, 1980

44. Soja PJ, Sinclair JG: Spinal vs supraspi­nal actions of morphine on cat spinal cord multireceptive neurons. Brain Res 273:1-7, 1983

45. Tessler A, Himes BT, Artymyshyn R, et al: Spinal neurons mediate return of sub­stance P following deafferentation of cat spinal cord. Brain Res 230:263-281, 1981

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47. Wood PL: Multiple opiate receptors: Support for unique mu, delta and kappa sites. Neuropharmacol 21:487-497, 1982

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336 PHYSICAL THERAPY