Pain

Plast Reconstr Surg. 2015 May;135(5):808e-17e. doi: 10.1097/PRS.0000000000001152.

Pulsed Electromagnetic Fields Reduce Postoperative Interleukin-1β, Pain, and Inflammation: A Double-Blind, Placebo-Controlled Study in TRAM Flap Breast Reconstruction Patients.

Rohde CH1, Taylor EM, Alonso A, Ascherman JA, Hardy KL, Pilla AA.

Author information

  • 1New York, N.Y. From the Division of Plastic and Reconstructive Surgery, Columbia University Medical Center; the Department of Biomedical Engineering, Columbia University; and the Department of Orthopedics, Mount Sinai School of Medicine.

Abstract

BACKGROUND:

Pulsed electromagnetic fields have been shown to reduce postoperative pain, inflammation, and narcotic requirements after breast reduction and augmentation surgical procedures. This study examined whether pulsed electromagnetic field therapy could produce similar results in patients undergoing unilateral transverse rectus abdominis myocutaneous (TRAM) flap breast reconstruction, a significantly more complex and painful surgical procedure.

METHODS:

In this double-blind, placebo-controlled, randomized study, 32 patients undergoing unilateral TRAM flap breast reconstruction received active or sham pulsed electromagnetic field therapy. Pain levels were measured by using a visual analogue scale; narcotic use and wound exudate volume were recorded starting 1 hour postoperatively. Wound exudates were analyzed for interleukin-1β.

RESULTS:

Mean visual analogue scale pain scores were 2-fold higher in the sham cohort at 5 hours and 4-fold higher at 72 hours (p < 0.01), along with a concomitant 2-fold increase in narcotic use in sham patients (p < 0.01). Wound exudate volume was 2-fold higher in the sham cohort at 24 hours (p < 0.01), and mean interleukin-1β concentration in wound exudates of sham patients was 5-fold higher at 24 hours (p < 0.001).

CONCLUSIONS:

Pulsed electromagnetic field therapy significantly reduced postoperative pain, inflammation, and narcotic use following TRAM flap breast reconstruction, paralleling its effect in breast reduction patients. Both studies also report a significant reduction of interleukin-1β in the wound exudate, supporting a mechanism involving a pulsed electromagnetic field effect on nitric oxide/cyclic guanosine monophosphate signaling, which modulates the body's antiinflammatory pathways. Adjunctive pulsed electromagnetic field therapy could impact the speed and quality of wound repair in many surgical procedures.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, I.

Adv Skin Wound Care.  2014 May;27(5):205-9. doi: 10.1097/01.ASW.0000445951.44967.ca.

The management of intractable pain with adjuvant pulsed electromagnetic field therapy.

Niezgoda JA1, Hardin ST, Kubat N, Acompanado J.
  • 1Jeffrey A. Niezgoda, MD, FACHM, MAPWCA, CHWS, is Associate Professor at the Medical College of Wisconsin, Milwaukee, Wisconsin. Scott T. Hardin, MD, is Medical Director of Rehabilitation Services at the Aurora St. Luke's Medical Center, Milwaukee, Wisconsin. Nicole Kubat, PhD, is an Independent Contract Consultant for Regenesis Biomedical, Inc, Scottsdale, Arizona. Jocelyn Acompanado, PA-C, is a Physician's Assistant in the Department of Rehabilitation Services at the Aurora St. Luke's Medical Center, Milwaukee, Wisconsin.

Abstract

This case describes a 51-year-old woman who reported experiencing severe, constant pain, diffusely located in the region of her right mandible neck (primarily involving the mandible, lower right molars, the neck, the upper back, and the shoulder) during the course of several years. Surgical interventions (root canal, spinal fusion) were performed to address potential sources of pain. Despite these interventions, the patient reported severe pain after both surgeries, which persisted beyond the acute postoperative period. Additional pharmacological interventions and physical therapy were also attempted; nonetheless, the patient reported that pain remained severe and constant for approximately 2 years. On the basis of the patient's poor response to conventional treatments, a novel approach of botulinum toxin (BTX) injections was initiated. When pulsed electromagnetic field therapy was added, the need for BTX injections decreased, with the patient reporting a noticeable decrease in pain intensity and an improvement in quality of life measures. Currently, the patient continues to use pulsed electromagnetic field therapy regularly for pain management, which has allowed her to reduce the use of other interventions and avoid continued use of narcotic medications. Considering the need for multifaceted pain management approaches in the treatment of chronic pain, this case is relevant for wound care practitioners attending to patients with chronic postincisional wound pain because the outcome highlights the utility of a nonpharmacological, complementary pain management intervention for closed, yet persistently painful, postoperative wounds.

West Indian Med J.  2013 Mar;62(3):205-9.

Evaluation of the efficacy of pulsed electromagnetic therapy in the treatment of back pain: a randomized controlled trial in a tertiary hospital in Nigeria.

Oke KI1, Umebese PF2.
  • 1Department of Physiotherapy, University of Benin Teaching Hospital, Benin City, Edo State, Nigeria. kayodeoke2001@yahoo.com
  • 2Department of Orthopaedics and Traumatology, University of Benin Teaching Hospital, Benin City, Edo State, Nigeria.

Abstract

Musculoskeletal system disorders (MSDs) are amongst the most commonly encountered problems in orthopaedics and physiotherapy practice all over the world and back pain is amongst the most prevalent of musculoskeletal presentations encountered in clinical practice. The attendant deformities, huge economic loss among many other sequelae on the affected individuals have always informed the search for cost-effective treatment modalities that are non-invasive and are devoid of or at least have minimal side effects. This randomized controlled trial was conducted to assess the therapeutic efficacy of the use of a non-pharmacological device [pulsed electromagnetic field (PEMF)] modality in the treatment of back pain. A total of 16 patients (mean age: 42.82 +/- 8.63 years) with back pain without radiculopathy who met the inclusion criteria were purposively enrolled in the study. Patients were randomly assigned into two groups. Group A had eight patients treated with PEMF plus medications (analgesics, nonsteroidal anti-inflammatory – diclofenac sodium) while the eight patients in group B were treated with only standard medications. The PEMF device was applied in group A four times a day for the period the patients were admitted (maximum of nine days). Measured outcome parameters were reduction in pain as assessed with numeric pain rating scale (NPRS) and improvement in functional ability status as assessed with functional activity scale (FAS). Obtained data were analysed with paired and independent t-test to test the significant efficacy of the treatment outcomes in the two groups. There was a statistically significant faster pain relief and resumption of active functions in patients treated with PEMF plus analgesic compared with the rates exhibited by patients treated with standard analgesics alone. These results suggest that PEMF therapy is beneficial in reducing pain and disability in patients with back pain and should be made part of holistic cape for back pain. Further studies using PEMF on larger patient populations are advocated to further confirm the efficacy of PEMF therapy in back pain management.

Rheumatol Int.  2012 Mar 27. [Epub ahead of print]

Non-invasive electromagnetic field therapy produces rapid and substantial pain reduction in early knee osteoarthritis: a randomized double-blind pilot study.

Nelson FR, Zvirbulis R, Pilla AA.

Source

Department of Orthopaedic Surgery, Henry Ford Hospital, CFP 644, 2799 West Grand Blvd., Detroit, MI, 48202, USA, fnelson1@hfhs.org.

Abstract

 

This study examined whether a non-thermal, non-invasive, pulsed electromagnetic field (PEMF), known to modulate the calmodulin (CaM)-dependent nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling pathway, could reduce pain in early knee OA. This randomized, placebo-controlled, double-blind pilot clinical study enrolled 34 patients. Patient selection required initial VAS ?4, 2 h of standing activity per day, and no recent interventions such as cortisone injections or surgery. Results showed VAS pain score decreased in the active cohort by 50 ± 11 % versus baseline starting at day 1 and persisting to day 42 (P < 0.001). There was no significant decrease in VAS versus baseline at any time point in the sham cohort (P = 0.227). The overall decrease in mean VAS score for the active cohort was nearly threefold that of the sham cohort (P < 0.001). The results suggest that non-thermal, non-invasive PEMF therapy can have a significant and rapid impact on pain from early knee OA and that larger clinical trials are warranted.

Photomed Laser Surg. 2010 Jun;28(3):371-7.

Pain threshold improvement for chronic hyperacusis patients in a prospective clinical study.

Zazzio M.

Audio Laser-Kliniken, Flygeln, Hovmantorp, Sweden. audiolaser@mail.nu

Abstract

OBJECTIVE: The aim of this study was to investigate if laser therapy in combination with pulsed electromagnetic field therapy/repetitive transcranial magnetic stimulation (rTMS) and the control of reactive oxygen species (ROS) would lead to positive treatment results for hyperacusis patients.

BACKGROUND DATA: Eight of the first ten patients treated for tinnitus, who were also suffering from chronic hyperacusis, claimed their hyperacusis improved. Based upon that, a prospective, unblinded, uncontrolled clinical trial was planned and conducted. ROS and hyperacusis pain thresholds were measured.

MATERIALS AND METHODS: Forty-eight patients were treated twice a week with a combination of therapeutic laser, rTMS, and the control and adjustment of ROS. A magnetic field of no more than 100 microT was oriented behind the outer ear, in the area of the mastoid bone. ROS were measured and controlled by administering different antioxidants. At every treatment session, 177-504 J of laser light of two different wavelengths was administered toward the inner ear via meatus acusticus.

RESULTS: The improvements were significantly better in the verum group than in a placebo group, where 40% of the patients were expected to have a positive treatment effect. The patients in the long-term follow-up group received significantly greater improvements than the patients in the short-term follow-up group.

CONCLUSION: The treatment is effective in treating chronic hyperacusis.

Plast Reconstr Surg. 2010 Jun;125(6):1620-9.

Effects of pulsed electromagnetic fields on interleukin-1 beta and postoperative pain: a double-blind, placebo-controlled, pilot study in breast reduction patients.

Rohde C, Chiang A, Adipoju O, Casper D, Pilla AA.

Division of Plastic and Reconstructive Surgery, Columbia University Medical Center, New York-Presbyterian Hospital, New York, NY 10032, USA. chr2111@columbia.edu

Abstract

BACKGROUND: Surgeons seek new methods of pain control to reduce side effects and speed postoperative recovery. Pulsed electromagnetic fields are effective for bone and wound repair and pain and edema reduction. This study examined whether the effect of pulsed electromagnetic fields on postoperative pain was associated with differences in levels of cytokines and angiogenic factors in the wound bed.

METHODS: In this double-blind, placebo-controlled, randomized study, 24 patients, undergoing breast reduction for symptomatic macromastia received pulsed electromagnetic field therapy configured to modulate the calmodulin-dependent nitric oxide signaling pathway. Pain levels were measured by a visual analogue scale, and narcotic use was recorded. Wound exudates were analyzed for interleukin (IL)-1 beta, tumor necrosis factor-alpha, vascular endothelial growth factor, and fibroblast growth factor-2.

RESULTS: Pulsed electromagnetic fields produced a 57 percent decrease in mean pain scores at 1 hour (p < 0.01) and a 300 percent decrease at 5 hours (p < 0.001), persisting to 48 hours postoperatively in the active versus the control group, along with a concomitant 2.2-fold reduction in narcotic use in active patients (p = 0.002). Mean IL-1 beta concentration in the wound exudates of treated patients was 275 percent lower (p < 0.001). There were no significant differences found for tumor necrosis factor-alpha, vascular endothelial growth factor, or fibroblast growth factor-2 concentrations.

CONCLUSIONS: Pulsed electromagnetic field therapy significantly reduced postoperative pain and narcotic use in the immediate postoperative period. The reduction of IL-1 beta in the wound exudate supports a mechanism that may involve manipulation of the dynamics of endogenous IL-1 beta in the wound bed by means of a pulsed electromagnetic field effect on nitric oxide signaling, which could impact the speed and quality of wound repair.

Indian J Exp Biol. 2009 Dec;47(12):939-48.

Low frequency pulsed electromagnetic field–a viable alternative therapy for arthritis.

Ganesan K, Gengadharan AC, Balachandran C, Manohar BM, Puvanakrishnan R.

Department of Biotechnology, Central Leather Research Institute, Adyar, Chennai 600 020, India.

Abstract

Arthritis refers to more than 100 disorders of the musculoskeletal system. The existing pharmacological interventions for arthritis offer only symptomatic relief and they are not definitive and curative. Magnetic healing has been known from antiquity and it is evolved to the present times with the advent of electromagnetism. The original basis for the trial of this form of therapy is the interaction between the biological systems with the natural magnetic fields. Optimization of the physical window comprising the electromagnetic field generator and signal properties (frequency, intensity, duration, waveform) with the biological window, inclusive of the experimental model, age and stimulus has helped in achieving consistent beneficial results. Low frequency pulsed electromagnetic field (PEMF) can provide noninvasive, safe and easy to apply method to treat pain, inflammation and dysfunctions associated with rheumatoid arthritis (RA) and osteoarthritis (OA) and PEMF has a long term record of safety. This review focusses on the therapeutic application of PEMF in the treatment of these forms of arthritis. The analysis of various studies (animal models of arthritis, cell culture systems and clinical trials) reporting the use of PEMF for arthritis cure has conclusively shown that PEMF not only alleviates the pain in the arthritis condition but it also affords chondroprotection, exerts antiinflammatory action and helps in bone remodeling and this could be developed as a viable alternative for arthritis therapy.

Int J Diabetes Dev Ctries. 2009 Apr;29(2):56-61.

Evaluation of the efficacy of pulsed electromagnetic field in the management of patients with diabetic polyneuropathy.

Graak V, Chaudhary S, Bal BS, Sandhu JS.

Department of Sports Medicine and Physiotherapy, Guru Nanak Dev University, Amritsar, Punjab, India.

Abstract

AIM: The study was carried out to evaluate and compare the effect of low power, low frequency pulsed electromagnetic field (PEMF) of 600 and 800 Hz, respectively, in management of patients with diabetic polyneuropathy. SETTINGS AND

DESIGNS: The study was a randomized controlled trial performed in Guru Nanak Dev University and Medical College, Amritsar, India with different subject experimental design.

MATERIALS AND METHODS: Thirty subjects within an age group of 40-68 years with diabetic polyneuropathy stages N1a, N1b, N2a were randomly allocated to groups 1, 2, 3 with 10 subjects in each. Group 1 and 2 were treated with low power 600 and 800-Hz PEMF for 30 min for 12 consecutive days. Group 3 served as control on usual medical treatment of diabetic polyneuropathy (DPN). The subjects with neuropathy due to any cause other than diabetes were excluded. The pain and motor nerve conduction parameters (distal latency, amplitude, nerve conduction velocity) were assessed before and after treatment.

STATISTICAL ANALYSIS: Related t-test and unrelated t-test were used for data analysis.

RESULTS: Significant reduction in pain and statistically significant (P<0.05) improvement in distal latency and nerve conduction velocity were seen in experimental group 1 and 2.

CONCLUSIONS: Low-frequency PEMF can be used as an adjunct in reducing neuropathic pain as well as for retarding the progression of neuropathy in a short span of time.

Bioelectromagnetics. 2008 May;29(4):284-95.

Electromagnetic millimeter wave induced hypoalgesia: frequency dependence and involvement of endogenous opioids.

Radzievsky AA, Gordiienko OV, Alekseev S, Szabo I, Cowan A, Ziskin MC.

Center for Biomedical Physics, Temple University Medical School, Philadelphia, Pennsylvania 19140, USA. aradziev@temple.edu

Abstract

Millimeter wave treatment (MMWT) is based on the systemic biological effects that develop following local skin exposure to low power electromagnetic waves in the millimeter range. In the present set of experiments, the hypoalgesic effect of this treatment was analyzed in mice. The murine nose area was exposed to MMW of “therapeutic” frequencies: 42.25, 53.57, and 61.22 GHz. MMWT-induced hypoalgesia was shown to be frequency dependent in two experimental models: (1) the cold water tail-flick test (chronic non-neuropathic pain), and (2) the wire surface test (chronic neuropathic pain following unilateral constriction injury to the sciatic nerve). Maximum hypoalgesic effect was obtained when the frequency was 61.22 GHz. Other exposure parameters were: incident power density = 13.3 mW/cm(2), duration of each exposure = 15 min. Involvement of delta and kappa endogenous opioids in the MMWT-induced hypoalgesia was demonstrated using selective blockers of delta- and kappa-opioid receptors and the direct ELISA measurement of endogenous opioids in CNS tissue. Possible mechanisms of the effect and the perspectives of the clinical application of MMWT are discussed.

Aesthetic Plast Surg. 2008 Jul;32(4):660-6. Epub 2008 May 28.

Effects of pulsed electromagnetic fields on postoperative pain: a double-blind randomized pilot study in breast augmentation patients.

Hedén P, Pilla AA.

Department of Plastic Surgery, Akademikliniken, Storängsvägen 10, 115 42, Stockholm, Sweden. per.heden@ak.se

Abstract

BACKGROUND: Postoperative pain may be experienced after breast augmentation surgery despite advances in surgical techniques which minimize trauma. The use of pharmacologic analgesics and narcotics may have undesirable side effects that can add to patient morbidity. This study reports the use of a portable and disposable noninvasive pulsed electromagnetic field (PEMF) device in a double-blind, randomized, placebo-controlled pilot study. This study was undertaken to determine if PEMF could provide pain control after breast augmentation.

METHODS: Forty-two healthy females undergoing breast augmentation for aesthetic reasons entered the study. They were separated into three cohorts, one group (n = 14) received bilateral PEMF treatment, the second group (n = 14) received bilateral sham devices, and in the third group (n = 14) one of the breasts had an active device and the other a sham device. A total of 80 breasts were available for final analysis. Postoperative pain data were obtained using a visual analog scale (VAS) and pain recordings were obtained twice daily through postoperative day (POD) 7. Postoperative analgesic medication use was also followed.

RESULTS: VAS data showed that pain had decreased in the active cohort by nearly a factor of three times that for the sham cohort by POD 3 (p < 0.001), and persisted at this level to POD 7. Patient use of postoperative pain medication correspondingly also decreased nearly three times faster in the active versus the sham cohorts by POD 3 (p < 0.001).

CONCLUSION: Pulsed electromagnetic field therapy, adjunctive to standard of care, can provide pain control with a noninvasive modality and reduce morbidity due to pain medication after breast augmentation surgery.

Knee Surg Sports Traumatol Arthrosc. 2007 Jul;15(7):830-4. Epub 2007 Feb 28.

Effects of pulsed electromagnetic fields on patients’ recovery after arthroscopic surgery: prospective, randomized and double-blind study.

Zorzi C, Dall’Oca C, Cadossi R, Setti S.

“Sacro Cuore Don Calabria” Hospital, Via don A. Sempreboni 5, 37024 Negrar (Vr), Italy.

Abstract

Severe joint inflammation following trauma, arthroscopic surgery or infection can damage articular cartilage, thus every effort should be made to protect cartilage from the catabolic effects of pro-inflammatory cytokines and stimulate cartilage anabolic activities. Previous pre-clinical studies have shown that pulsed electromagnetic fields (PEMFs) can protect articular cartilage from the catabolic effects of pro-inflammatory cytokines, and prevent its degeneration, finally resulting in chondroprotection. These findings provide the rational to support the study of the effect of PEMFs in humans after arthroscopic surgery. The purpose of this pilot, randomized, prospective and double-blind study was to evaluate the effects of PEMFs in patients undergoing arthroscopic treatment of knee cartilage. Patients with knee pain were recruited and treated by arthroscopy with chondroabrasion and/or perforations and/or radiofrequencies. They were randomized into two groups: a control group (magnetic field at 0.05 mT) and an active group (magnetic field of 1.5 mT). All patients were instructed to use PEMFs for 90 days, 6 h per day. The patients were evaluated by the Knee injury and Osteoarthritis Outcome Score (KOOS) test before arthroscopy, and after 45 and 90 days. The use of non-steroidal anti-inflammatory drugs (NSAIDs) to control pain was also recorded. Patients were interviewed for the long-term outcome 3 years after arthroscopic surgery. Thirty-one patients completed the treatment. KOOS values at 45 and 90 days were higher in the active group and the difference was significant at 90 days (P < 0.05). The percentage of patients who used NSAIDs was 26% in the active group and 75% in the control group (P = 0.015). At 3 years follow-up, the number of patients who completely recovered was higher in the active group compared to the control group (P < 0.05). Treatment with I-ONE aided patient recovery after arthroscopic surgery, reduced the use of NSAIDs, and also had a positive long-term effect.

Neurosci Biobehav Rev. 2007;31(4):619-42. Epub 2007 Feb 14.

Pain perception and electromagnetic fields.

Del Seppia C, Ghione S, Luschi P, Ossenkopp KP, Choleris E, Kavaliers M.

Institute of Clinical Physiology, National Council of Research, Pisa, Italy. dscri@ifc.cnr.it

Abstract

A substantial body of evidence has accumulated showing that exposure to electromagnetic fields (EMFs) affects pain sensitivity (nociception) and pain inhibition (analgesia). Consistent inhibitory effects of acute exposures to various EMFs on analgesia have been demonstrated in most studies. This renders examinations of changes in the expression of analgesia and nociception a particularly valuable means of addressing the biological effects of and mechanisms underlying the actions of EMFs. Here we provide an overview of the effects of various EMFs on nociceptive sensitivity and analgesia, with particular emphasis on opioid-mediated responses. We also describe the analgesic effects of particular specific EMFs, the effects of repeated exposures to EMFs and magnetic shielding, along with the dependence of EMF effects on lighting conditions. We further consider some of the underlying cellular and biophysical mechanisms along with the clinical implications of these effects of various EMFs.

Wiad Lek. 2006;59(9-10):630-3.

Comparison of analgetic effect of magnetic and laser stimulation before oral surgery procedures.

[Article in Polish]

Koszowski R, Smieszek-Wilczewska J, Dawiec G.

Z Katedry i Zak?adu Chirurgii Stomatologicznej w Bytomiu Slaskiej Akademii Medycznej w Katowicach. chirstom@slam.katowice.pl

Abstract

Oral surgery procedures are often the cause of painful sensations because of their tissue invasiveness. To avoid these sensations a wide use of nonsteroid antiinflammatory drugs is usually accepted. Because of plenty side effects of these drugs alternative antipain agents are desired. The goal of this study was to assess antipain effect of laser stimulation and alternating magnetic field in oral surgery procedures. Pain sensations in patients during: local anesthetics application, surgical procedure and after it were assessed according to VAS scale. Level of stomatological fear was assessed with the use of Corah’s scale. Achieved results were analyzed statistically. Conclusion of this analysis is that laser stimulation and alternating magnetic field applied directly before oral surgery procedure are effective antipain agents that decrease intra and postoperative sensations. It was observed that patients with high level of stomatological fear had more pain sensations but even in this group laser and magnetic stimulation significantly lowered these complaints.

Evid Based Complement Alternat Med. 2006 Jun;3(2):201-7. Epub 2006 Apr 24.

Low-intensity electromagnetic millimeter waves for pain therapy.

Usichenko TI, Edinger H, Gizhko VV, Lehmann C, Wendt M, Feyerherd F.

Abstract

Millimeter wave therapy (MWT), a non-invasive complementary therapeutic technique is claimed to possess analgesic properties. We reviewed the clinical studies describing the pain-relief effect of MWT. Medline-based search according to review criteria and evaluation of methodological quality of the retrieved studies was performed. Of 13 studies, 9 of them were randomized controlled trials (RCTs), only three studies yielded more than 3 points on the Oxford scale of methodological quality of RCTs. MWT was reported to be effective in the treatment of headache, arthritic, neuropathic and acute postoperative pain. The rapid onset of pain relief during MWT lasting hours to days after, remote to the site of exposure (acupuncture points), was the most characteristic feature in MWT application for pain relief. The most commonly used parameters of MWT were the MW frequencies between 30 and 70 GHz and power density up to 10 mW cm(-2). The promising results from pilot case series studies and small-size RCTs for analgesic/hypoalgesic effects of MWT should be verified in large-scale RCTs on the effectiveness of this treatment method.

Australas Psychiatry. 2005 Sep;13(3):258-65.  

Transcranial magnetic stimulation and chronic pain: current status.

Pridmore S, Oberoi G, Marcolin M, George M.

Division of Psychiatry, University of Tasmania, Hobart, Tas., Australia. spridmore@iprimus.com.au

OBJECTIVE: To examine evidence suggesting a potential role for transcranial magnetic stimulation (TMS) in the treatment of chronic pain. CONCLUSION: Chronic pain is characterized by brain changes that can reasonably be presumed to be associated with hyperalgesia, as occurs with neuropathic changes in the periphery. TMS has the ability to induce plastic changes in the cortex at the site of stimulation and at connected sites, including the spinal cord. It also has the ability to influence the experience of experimental/acute pain. In studies of TMS in chronic pain, there is some evidence that temporary relief can be achieved in a proportion of sufferers. Chronic pain is common. Current treatments are often ineffective and complicated by side-effects. Work to this point is encouraging, but systematic assessment of stimulation parameters is necessary if TMS is to achieve a role in the treatment of chronic pain. Maintenance TMS is currently provided in relapsing major depression and may be a useful model in chronic pain management.

Bioelectromagnetics. 2004 Sep;25(6):466-73.

Millimeter wave-induced suppression of B16 F10 melanoma growth in mice: involvement of endogenous opioids.

Radzievsky AA, Gordiienko OV, Szabo I, Alekseev SI, Ziskin MC.

Center for Biomedical Physics, Temple University Medical School, Philadelphia, Pennsylvania 19140, USA. aradziev@temple.edu

Abstract

Millimeter wave treatment (MMWT) is widely used in Eastern European countries, but is virtually unknown in Western medicine. Among reported MMWT effects is suppression of tumor growth. The main aim of the present “blind” and dosimetrically controlled experiments was to evaluate quantitatively the ability of MMWT to influence tumor growth and to assess whether endogenous opioids are involved. The murine experimental model of B16 F10 melanoma subcutaneous growth was used. MMWT characteristics were: frequency, 61.22 GHz; average incident power density, 13.3 x 10(-3) W/cm2; single exposure duration, 15 min; and exposure area, nose. Naloxone (1 mg/kg, intraperitoneally, 30 min prior to MMWT) was used as a nonspecific blocker of opioid receptors. Five daily MMW exposures, if applied starting at the fifth day following B16 melanoma cell injection, suppressed subcutaneous tumor growth. Pretreatment with naloxone completely abolished the MMWT-induced suppression of melanoma growth. The same course of 5 MMW treatments, if started on day 1 or day 10 following tumor inoculations, was ineffective. We concluded that MMWT has an anticancer therapeutic potential and that endogenous opioids are involved in MMWT-induced suppression of melanoma growth in mice. However, appropriate indications and contraindications have to be developed experimentally before recommending MMWT for clinical usage.

Neurosci Lett. 2004 Jun 10;363(2):157-62.  

Human exposure to a specific pulsed magnetic field: effects on thermal sensory and pain thresholds.

Shupak NM, Prato FS, Thomas AW.

Department of Nuclear Medicine, St Joseph’s Health Care, London, Ontario, Canada.

Exposure to pulsed magnetic fields (MF) has been shown to have a therapeutic benefit in both animals (e.g. mice, snails) and humans. The current study investigated the potential analgesic benefit of MF exposure on sensory and pain thresholds following experimentally induced warm and hot sensations. Thirty-nine subjects (Study 1) and 31 subjects (Study 2) were randomly and double-blindly assigned to 30 min of MF or sham exposure between two sets of tests of sensory and pain thresholds and latencies at, 1 degrees C above, and 2 degrees C above pain thresholds. Results indicated that MF exposure does not affect sensory thresholds [e.g. [F(1,31) = 0.073, NS]. Pain thresholds were significantly increased following MF exposure [F(1,6) = 9.45, P < 0.01] but not following sham exposure [F (1,4) = 4.22, NS]. A significant condition by gender interaction existed for post-exposure pain thresholds [F(1,27) = 5.188, P < 0.05]. Taken together, these results indicate that MF exposure does not affect basic human perception, but can increase pain thresholds in a manner indicative of an analgesic response. The potential involvement of the placebo effect is discussed.

Suppl Clin Neurophysiol. 2004;57:737-48.  

Transcranial magnetic stimulation in the management of pain.

Lefaucheur JP.

Service de Physiologie, Explorations Fonctionnelles, Hopital Henri Mondor, Assistance Publique, Hopitaux de Paris, INSERM U421, Faculte de Medecine de Creteil, 94010 Creteil, France. jean-pascal.lefaucheur@hmn.ap-hop-paris.fr

Drug-resistant, neurogenic pain can be treated by chronic motor cortex stimulation using surgically-implanted epidural electrodes. High-frequency, subthreshold repetitive transcranial magnetic stimulation (rTMS) of the motor cortex was shown to be able to produce antalgic effects, at least transiently, in patients with chronic pain. Nevertheless, other cortical targets than the primary motor cortex are tempting (parietal or prefrontal areas for instance) for the management of pain and need to be studied. Motor cortex TMS was also found to modulate non-nociceptive sensory perception as well as acutely provoked pain in healthy subjects by means of a single conditioning pulse or repeated trains. On the contrary, spontaneous or provoked pain was shown to modify motor cortex excitability, as assessed by TMS technique. Taking into account all these observations, it appears that motor cortex function and pain process are closely related and that TMS is a potent tool to explore and to understand this relationship. Beyond this physiological purpose, rTMS could be useful to control episodes of neurogenic pain of limited duration or to select patients for the surgical implantation of a cortical stimulator.

Neurosci Lett. 2004 Jan 2;354(1):30-3.

Analgesic and behavioral effects of a 100 microT specific pulsed extremely low frequency magnetic field on control and morphine treated CF-1 mice.

Shupak NM, Hensel JM, Cross-Mellor SK, Kavaliers M, Prato FS, Thomas AW.

Bioelectromagnetics, Lawson Health Research Institute, Department of Nuclear Medicine, St. Joseph’s Health Care, 268 Grosvenor Street, London, Ont. N6A 4V2, Canada.

Abstract

Diverse studies have shown that magnetic fields can affect behavioral and physiological functions. Previously, we have shown that sinusoidal extremely low frequency magnetic fields and specific pulsed magnetic fields (Cnps) can produce alterations in the analgesia-related behavior of the land snail. Here, we have extended these studies to show an induction of analgesia in mice equivalent to a moderate dose of morphine (5 mg/kg), and the effect of both Cnp exposure and morphine injection on some open-field activity. Cnp exposure was found to prolong the response latency to a nociceptive thermal stimulus (hot plate). Cnp+morphine offset the increased movement activity found with morphine alone. These results suggest that pulsed magnetic fields can induce analgesic behavior in mice without the side effects often associated with opiates like morphine.

Acupunct Electrother Res. 2003;28(1-2):11-8.

Treatment of rheumatoid arthritis with electromagnetic millimeter waves applied to acupuncture points–a randomized double blind clinical study.

Usichenko TI, Ivashkivsky OI, Gizhko VV.

Anesthesiology & Intensive Care Medicine Department, University of Greifswald, Germany. taras@uni-greifswald.de

Abstract

The aim of the study was to evaluate the efficacy and safety of electromagnetic millimeter waves (MW) applied to acupuncture points in patients with rheumatoid arthritis (RA). Twelve patients with RA were exposed to MW with power 2.5 mW and band frequency 54-64 GHz. MW were applied to the acupuncture points of the affected joints in a double blind manner. At least 2 and maximum 4 points were consecutively exposed to MW during one session. Total exposure time consisted of 40 minutes. According to the study design, group I received only real millimeter wave therapy (MWT) sessions, group II only sham sessions. Group III was exposed to MW in a random cross-over manner. Pain intensity, joint stiffness and laboratory parameters were recorded before, during and immediately after the treatment. The study was discontinued because of beneficial therapeutic effects of MWT. Patients from group I (n=4) reported significant pain relief and reduced joint stiffness during and after the course of therapy. Patients from group II (n=4) revealed no improvement during the study. Patients from group III reported the changes of pain and joint stiffness only after real MW sessions. After further large-scale clinical investigations MWT may become a non-invasive adjunct in therapy of patients with RA.

Eur J Pain. 2003;7(3):289-94.

Treatment of chronic pain with millimetre wave therapy (MWT) in patients with diffuse connective tissue diseases: a pilot case series study.

Usichenko TI, Herget HF.

Department of Anaesthesiology and Intensive Care, Ernst Moritz Arndt University, Friedrich Loeffler Strasse 23b, 17487 Greifswald, Germany.taras@uni-greifswald.de

Abstract

BACKGROUND: Pain relief is reported to be the most common clinical application of electromagnetic millimetre waves.

AIM: To evaluate safety and pain relief effect of millimetre wave therapy (MWT) for treatment of chronic joint pain in a group of patients with diffuse connective tissue diseases.

METHODS: Twelve patients with diffuse connective tissue diseases received MWT in addition to their analgesic medication with non-steroidal anti-inflammatory drugs. MWT procedure included the exposure of tender points around the painful joints to electromagnetic waves with frequency 54-78GHz and power density of 2.5mW/cm(2). The time of exposure was 35 +/-5 min and the total number of sessions ranged from 5 to 10 (median 6). Intensity of pain, medication requirement, joint stiffness and subjective assessment of therapy success were measured before, during and immediately after the treatment, and after a 6-months follow-up.

RESULTS: No adverse effects of MWT were noted. Pain intensity and required medication decreased significantly after the treatment (p<0.05) and remained at the same level throughout the follow-up period. The joint stiffness decreased and the subjective assessment of the treatment success after 6 month did not change except in only one patient.

CONCLUSION: MWT applied to tender points around the affected joints was safe under the conditions of our study and after an appropriate full-scale double-blind clinical study, may be recommended as an effective adjunct therapy for chronic pain treatment in patients with diffuse connective tissue diseases.

Percept Mot Skills. 2002 Oct;95(2):592-8.  

Increased analgesia to thermal stimuli in rats after brief exposures to complex pulsed 1 microTesla magnetic fields.

Ryczko MC, Persinger MA.

Behavioral Neuroscience Program, Laurentian University, Sudbury, ON, Canada.

Nociceptive thresholds to a 55 degrees C hot surface were measured for female Wistar rats before treatments and 30 min. and 60 min. after the treatments. After injection with either naloxone or saline following baseline measurements, the rats were exposed for 30 min. to either sham fields or to weak (about 1 microTesla) burst-firing magnetic fields composed of 230 points (4 msec. per point) presented once every 3 sec. The rats that had received the burst-firing magnetic fields exhibited elevated nociceptive thresholds that explained about 50% of the variance. A second pattern, designed after the behaviour of individual thalamic neurons during nociceptive input and called the “activity rhythm magnetic field” produced only a transient analgesic effect. These results replicated previous studies and suggest that weak, extremely low frequency, pulsed magnetic fields with biorelevant temporal structures may have utility as adjuncts for treatment of pain.

Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 2001 Dec;18(4):552-3, 572.  

Analgesic effect induced by stimulation of rats brain with strong pulsed magnetic field: a preliminary study.

[Article in Chinese]

Wang Y, Niu J. Shen Q, Jiang D.

Institute of Biomedical Engineering, Xi’an Jiaotong University, Xi’an 710049.

The Objective of this study was to determine whether stimulation on the brain of SD rats with strong pulsed magnetic field could produce analgesic effect. A stimulator of CADWELL (MES-10) was adopted in the study. The pain index used was the Tail Flick Latency (TFL) of rats. The stimulation parameters were: (1) the intensity percent (20%) and stimulation duration (7 min); (2) the intensity percent (30%) and stimulation duration (3 min). The results showed that the mean Acquired TFL change was 23% (P < 0.01) for the 20% intensity group, and 26% (P < 0.01) for the 30% intensity group. CONCLUSION: These data indicate that the new method for analgesia is effective, and compared with other approaches to stimulation analgesia, this one is non-invasive, easy to operate, and less causative of discomfort.

Life Sci. 2001 Jan 26;68(10):1143-51.

Peripheral neural system involvement in hypoalgesic effect of electromagnetic millimeter waves.

Radzievsky AA, Rojavin MA, Cowan A, Alekseev SI, Radzievsky AA Jr, Ziskin MC.

Center for Biomedical Physics, Temple University School of Medicine, Philadelphia, PA 19140, USA. aradziev@temple.edu

Abstract

In a series of blind experiments, using the cold water tail-flick test (cTFT) as a quantitative indicator of pain, the hypoalgesic effect of a single exposure of mice to low power electromagnetic millimeter waves (MW) was studied. The MW exposure characteristics were: frequency = 61.22 GHz; incident power density = 15 mW/cm2; and duration = 15 min. MW treatment was applied to the glabrous skin of the footpad. Exposure of an intact murine paw to the MW resulted in a statistically significant hypoalgesia as measured in the cTFT. These mice were able to resist cold noxious stimulation in the cTFF more than two times longer than animals from the sham-exposed group. A unilateral sciatic nerve transection was used to deafferent the area of exposure in animals from one of the experimental groups. This surgery, conducted six days before the MW treatment, completely abolished the hypoalgesic effect of the exposure to MW. The results obtained support the conclusion that the MW-skin nerve endings interaction is the essential step in the initiation of biological effects caused by MW. Based on our past and present results we recommend that in order to obtain a maximum therapeutic effect, densely innervated skin areas (head, hands) need to be used preferentially for exposure to MW in clinical practice.

Vopr Kurortol Fizioter Lech Fiz Kult. 2000 Jul-Aug;(4):7-11.

Pain relief by low-intensity frequency-modulated millimeter waves acting on the acupuncture points.

[Article in Russian]

Samosiuk IZ, Kulikovich IuN, Tamarova ZA, Samosiuk NI, Kazhanova AK.

Abstract

Analgetic effect of low-intensive frequency-modulated millimetric waves (MW) was studied in mice with formalin induced nociceptive behavior reaction (licking of defeat hindpaw). MW were applied to the acupoint E 36 of the defeat hindpaw. The following MW were used: 60 GHz (1) and 118 GHz (2) which were modulated by 4 Hz; noise MW within the range of 42-95 GHz (3) and 90-140 GHz (4) which were modulated in accidental order by frequencies 1-60 Hz; combinations of fixed frequencies with noise – 60 GHz + noise 42-95 GHz (5) and 118 GHz + noise 90-140 GHz (6). All used MW combinations suppressed licking of the defeat hindpaw and increased duration of sleep and eating. The strongest analgesia was achieved in series 1-3 (42.4-69.7%), the weakest in series 6 and 4 of the experiment (12.2-19.7%).

Int J Radiat Biol. 2000 Apr;76(4):575-9.

Pain relief caused by millimeter waves in mice: results of cold water tail flick tests.

Rojavin MA, Radzievsky AA, Cowan A, Ziskin MC.

Richard J Fox Center for Biomedical Physics, Philadelphia, PA 19140, USA.

Abstract

PURPOSE: To find out if millimeter waves can decrease experimental pain response in mice using cold water tail flick test.

MATERIALS AND METHODS: Male Swiss albino mice (15 mice per group) were exposed to continuous millimeter waves at a frequency of 61.22 GHz with incident power densities (IPD) ranging from 0.15 to 5.0 mW/cm2 for 15 min or sham exposed. Latency of tail withdrawal in a cold water (1 +/- 0.5 degrees C) tail flick test was measured before the exposure (baseline) and then four times after the exposure with 15 min breaks.

RESULTS: The mean latency of the tail flick response in mice exposed to millimeter waves was more than twice that of sham-exposed controls (p<0.05). This effect was proportional to the power of millimeter waves and completely disappeared at an IPD level of < or = 0.5 mW/cm2. Pretreatment of mice with the opioid antagonist naloxone (1 mg/kg i.p.) blocked the effect of millimeter waves.

CONCLUSIONS: Results suggest that the antinociceptive effect of millimeter waves is mediated through endogenous opioids.

Life Sci. 2000 Apr 14;66(21):2101-11.

Hypoalgesic effect of millimeter waves in mice: dependence on the site of exposure.

Radzievsky AA, Rojavin MA, Cowan A, Alekseev SI, Ziskin MC.

Center for Biomedical Physics, Temple University School of Medicine, Philadelphia, PA 19140, USA. aradziev@temple.edu

Abstract

Based on a hypothesis of neural system involvement in the initial absorption and further processing of the millimeter electromagnetic waves (MW) signal, we reproduced, quantitatively assessed and compared the analgesic effect of a single MW treatment, exposing areas of skin possessing different innervation densities. The cold water tail flick test (cTFT) was used to assess experimental pain in mice. Three areas of exposure were used: the nose, the glabrous skin of the right footpad, and the hairy skin of the mid back at the level of T5-T10. The MW exposure characteristics were: frequency = 61.22 GHz; incident power density = 15mW/cm2; and duration = 15 min. The maximum hypoalgesic effect was achieved by exposing to MW the more densely innervated skin areas–the nose and the footpad. The hypoalgesic effect in the cTFT after MW exposure to the murine back, which is less densely innervated, was not statistically significant. These results support the hypothesis of neural system involvement in the systemic response to MW.

Int J Radiat Biol. 1997 Oct;72(4):475-80.

Electromagnetic millimeter waves increase the duration of anaesthesia caused by ketamine and chloral hydrate in mice.

Rojavin MA, Ziskin MC.

Richard J. Fox Center for Biomedical Physics, Temple University School of Medicine, Philadelphia, PA 19140, USA.

Abstract

BALB/c mice were injected i.p. with either ketamine 80 mg/kg or chloral hydrate 450 mg/kg. Anaesthetized mice were exposed to unmodulated electromagnetic millimeter waves at the frequency of 61.22 GHz with a peak specific absorption rate of 420 W/kg and corresponding incident power density of 15 mW/cm2 for 15 min or sham-exposed. In combination with either of the anaesthetics used, mm waves increased the duration of anaesthesia by approximately 50% (p < 0.05) in a dose (power)-dependent manner. Sham exposure to mm waves did not affect the sleeping time of mice. Pretreatment of mice with naloxone, an opioid antagonist, did not change the duration of anaesthesia caused by the corresponding chemical agent, but completely blocked or decreased the additional effect of mm waves. The data in this study indicates that exposure of mice to mm waves in vivo releases endogenous opioids or enhances the activity of opioid signalling pathway.

Neurosci Lett. 1997 Jan 31;222(2):107-10.

Antinociceptive effects of a pulsed magnetic field in the land snail, Cepaea nemoralis.

Thomas AW, Kavaliers M, Prato FS, Ossenkopp KP.

Neuroscience Program, University of Western Ontario, London, Canada. athomas@Iri.stjoseph-s.london.on.ca

Abstract

Pulsed magnetic fields (patent pending) consisting of approximately 100 microT (peak), frequency modulated, extremely low frequency magnetic fields (ELFMF) were shown to induce a significant degree of antinociception (‘analgesia’) in the land snail Cepaea nemoralis. Fifteen minute exposures to a specific magnetic field both increased enkephalinase inhibitor induced opioid analgesia and induced analgesia in untreated snails. Injection of the prototypic opioid antagonist naloxone, attenuated, but did not completely block, the pulsed magnetic field induced analgesia. Two other pulsed waveform designs failed to induce analgesia in untreated snails. These findings suggest that specific magnetic field exposure designs may be tailored to produce significant behavioral effects including, but certainly not limited to, the induction of analgesia.

FASEB J. 1995 Jun;9(9):807-14.

Possible mechanisms by which extremely low frequency magnetic fields affect opioid function.

Prato FS, Carson JJ, Ossenkopp KP, Kavaliers M.

Department of Medical Biophysics, University of Western Ontario, London, Canada.

Abstract

Although extremely low frequency (ELF, < 300 Hz) magnetic fields exert a variety of biological effects, the magnetic field sensing/transduction mechanism (or mechanisms) remain to be identified. Using the well-defined inhibitory effects that magnetic fields have on opioid peptide mediated antinociception or “analgesia” in the land snail Cepaea nemoralis, we show that these actions only occur for certain frequency and amplitude combinations of time-varying sinusoidal magnetic fields in a manner consistent with a direct influence of these fields. We exposed snails with augmented opioid activity to ELF magnetic fields, which were varied in both amplitude and frequency, along with a parallel static magnetic field. When the peak amplitude (0-547 microT) of a magnetic field of 60 Hz was varied systematically, we observed a nonlinear response, i.e., a nonlinear reduction in analgesia as measured by the latency of a defined response by the snails to a thermal stimulus. When frequency (10-240 Hz) was varied, keeping the amplitude constant (141 microT), we saw significant inhibitory effects between 30 and 35 Hz, 60 and 90 Hz and at 120 and 240 Hz. Finally, when the static field was varied but the amplitude and frequency of the time-varying field were held constant, we observed significant inhibition at almost all amplitudes. This amplitude/frequency “resonance-like” dependence of the magnetic field effects suggests that the mechanism (or mechanisms) of response to weak ELF fields likely involves a direct magnetic field detection mechanism rather than an induced current phenomenon. We examined the implications of our findings for several models proposed for the direct sensing of ELF magnetic fields.

Brain Res. 1993 Aug 20;620(1):159-62.

Repeated naloxone treatments and exposures to weak 60-Hz magnetic fields have ‘analgesic’ effects in snails.

Kavaliers M, Ossenkopp KP.

Bioelectromagnetics Western and Neuroscience Program, University of Western Ontario, London, Canada.

Abstract

Results of studies with rodents have shown that animals repeatedly injected with the opioid antagonist, naloxone, acquire a hypoalgesic response to thermal nociceptive stimuli. The present study revealed a similar response in the terrestrial pulmonate snail, Cepaea nemoralis. Snails receiving daily injections of naloxone followed by measurements of thermal nociceptive sensitivity also developed hypoalgesia. Daily brief (30-min) exposures to a weak 60-Hz magnetic field (1.0 gauss or 0.1 mT), which acutely antagonize opioid-mediated nociception and antinociception in a manner comparable to that of naloxone, also led to the expression of a hypoalgesic responses. This suggests that opioid antagonist-induced thermal hypoalgesia may be a basic feature of opioid systems. This naloxone- and magnetic field-induced ‘analgesia’ is consistent with either a facilitation of aversive thermal conditioning and or antagonism of the excitatory, hyperalgesic effects of low levels of endogenous opioids.

Minerva Anestesiol. 1989 Jul-Aug;55(7-8):295-9.  

Pulsed magnetic fields.  Observations in 353 patients suffering from chronic pain

[Article in Italian]

Di Massa A, Misuriello I, Olivieri MC, Rigato M.

Three hundred-fifty-three patients with chronic pain have been treated with pulsed electromagnetic fields. In this work the Authors show the result obtained in the unsteady follow-up (2-60 months). The eventual progressive reduction of benefits is valued by Spearman’s test. We noted the better results in the group of patients with post-herpetic pain (deafferentation) and in patients simultaneously suffering from neck and low back pain.

J Comp Physiol A. 1988 Mar;162(4):551-8.

Magnetic fields inhibit opioid-mediated ‘analgesic’ behaviours of the terrestrial snail, Cepaea nemoralis.

Kavaliers M, Ossenkopp KP.

Division of Oral Biology, Faculty of Dentistry, University of Western Ontario, London, Canada.

Abstract

1. The terrestrial snail, Cepaea nemoralis, when placed on a warmed surface (40 degrees C) displays a thermal avoidance behaviour that entails an elevation of the anterior portion of the fully extended foot. The latency of this nociceptive response was increased by the prototypical mu and specific kappa opiate agonists, morphine and U-50, 488H, respectively, in a manner indicative of anti-nociception and the induction of ‘analgesia’. Pretreatment with the prototypical opiate antagonist, naloxone, blocked the morphine- and reduced the U-50, 488H-induced analgesia. Naloxone had no effects on the thermal response latencies of saline treated animals. 2. Exposure to either cold (7 degrees C) or warm (38 degrees C) temperature stress increased the nociceptive thresholds of Cepaea in a manner indicative of the induction of ‘stress-induced analgesia’. The warm stress-induced analgesia was opioid mediated, being blocked by naloxone, whereas, the cold stress-induced analgesia was insensitive to naloxone. 3. Exposure for 15-30 min to 0.5 Hz weak rotating magnetic fields (1.5-8.0 G) significantly reduced the analgesic effects of the mu and kappa opiate agonists in a manner similar to that observed with naloxone. The magnetic stimuli also inhibited the endogenous opioid mediated warm stress-induced analgesia and significantly reduced the cold stress-induced analgesia. The magnetic stimuli had no evident effects on the nociceptive responses of saline-treated animals. The dihydropyridine (DHP) and non-DHP calcium channel antagonists diltiazem, verapamil. and nifedipine differentially and significantly reduced, while the DHP calcium channel agonist, BAY K8644, significantly enhanced the inhibitory effects of the magnetic fields on morphine-induced analgesia.

Peptides. 1986 May-Jun;7(3):449-53.

Magnetic fields differentially inhibit mu, delta, kappa and sigma opiate-induced analgesia in mice.

Kavaliers M, Ossenkopp KP.

Abstract

An exposure for 60 min to a 0.5 Hz rotating magnetic field (1.5-90 G) significantly attenuated the daytime analgesic effects of the mu and kappa opiate agonists, morphine and U50,488H, respectively, and significantly inhibited the analgesic actions of the delta agonist, D-Ala2-D-Leu5-enkephalin, in mice. The magnetic stimuli had no significant effects on the analgesic effects of the prototypic sigma opiate agonist (+/-) SKF-10,047. These results show that exposure to relatively weak magnetic stimuli has significant and differential inhibitory influences on various opioid systems.