Electroacupuncture alleviates chemotherapy-induced pain through inhibiting phosphorylation of spinal CaMKII in rats.

BACKGROUND: Current medical treatments for chemotherapy-induced pain (CIP) are either ineffective or have adverse side effects. Acupuncture may alleviate CIP, but its effectiveness against this condition has not been studied. Paclitaxel causes neuropathic pain in cancer patients. METHODS: We evaluated the effects of electroacupuncture (EA) on paclitaxel-induced CIP in a rat model. Paclitaxel (2 mg/kg) or vehicle was injected (i.p.) on alternate days of 0-6. The resulting pain was treated with 10 Hz/2 mA/0.4 ms pulse EA for 30 min at the equivalent of human acupoint GB30 (Huantiao) once every other day between days 14 and 26. For sham control, EA needles were inserted into GB30 without stimulation. Von Frey filaments with bending forces of 2-8 g and 15 g were used to assess mechanical allodynia and hyperalgesia, respectively, on day 13 and once every other day between 14-26 days and then for 2-3 weeks after EA treatment. RESULTS: Compared to sham control, EA significantly alleviated paclitaxel-induced mechanical allodynia and hyperalgesia, as shown by less frequent withdrawal responses to the filaments. The alleviation of allodynia/hyperalgesia lasted up to 3 weeks after the EA treatment. EA significantly inhibited phosphorylation of Ca2+ /calmodulin-dependent protein kinase II (CaMKII) in the spinal cord. KN-93, a selective inhibitor of p-CaMKII, inhibited mechanical allodynia/hyperalgesia and p-CaMKII. 5-HT1A receptor antagonist blocked EA inhibition of allodynia/hyperalgesia and p-CaMKII. CONCLUSIONS: Electroacupuncture activates 5-HT 1A receptors in the spinal cord and inhibits p-CaMKII to alleviate both allodynia and hyperalgesia. The data support acupuncture/EA as a complementary therapy for CIP. SIGNIFICANCE: Electroacupuncture (EA) activates spinal 5-HT1A receptors to inhibit p-CaMKII to alleviate paclitaxel-induced pain. Acupuncture/EA may be used as a complementary therapy for CIP.

DAMGO in the central amygdala alleviates the affective dimension of pain in a rat model of inflammatory hyperalgesia.

Pain has sensory-discriminative and emotional-affective dimensions. Recent studies show that the affective component can be assessed with a conditioned place avoidance (CPA) test. We hypothesized that systemic morphine before a post-conditioning test would more potently attenuate the affective aspect compared to the sensory component and that [d-Ala2-N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO), a µ-selective opioid receptor agonist, injected into the central nucleus of the amygdala (CeA) would reduce established CPA. A rat model of inflammatory pain, produced by a complete Freund adjuvant (CFA) injection into the hind paw, was combined with a CPA test. Three experiments were performed on adult male Sprague-Dawley rats. Systemic morphine (0.5 or 1.0mg/kg) in Experiment 1, intrathecal (i.t.) morphine (2.5 µg/rat) in Experiment 2, and intra-CeA DAMGO (7.7-15.4 ng/0.4 µl) in Experiment 3 were given to CFA-injected rats (n=6-8/group) prior to a post-conditioning test. Saline-injected rats were used as control. Time spent in a pain-paired compartment was recorded twice, before conditioning and after a post-conditioning test. Paw withdrawal latency (PWL) to a noxious thermal stimulus was measured before experiment at day-1 and after the post-conditioning test; hyperalgesia was defined as a decrease in PWL. The data showed that CFA-injected rats had significantly negative CPA compared to those of saline-injected rats (P<0.05). Low-dosage systemic morphine significantly (P<0.05) reduced CFA-induced CPA but had no effect on PWL. I.t. morphine did not inhibit the display of CPA but significantly increased PWL, suppressing hyperalgesia (P<0.05). Intra-CeA DAMGO significantly inhibited the display of CPA compared to saline (P<0.05) but had no effect on PWL. The data demonstrate that morphine attenuates the affective component more powerfully than it does the sensory and suggests that the sensory and the emotional-affective dimensions are underpinned by different mechanisms.

Electroacupuncture inhibition of hyperalgesia in an inflammatory pain rat model: involvement of distinct spinal serotonin and norepinephrine receptor subtypes.

BACKGROUND: Although acupuncture analgesia is well documented, its mechanisms have not been thoroughly clarified. We previously showed that electroacupuncture (EA) activates supraspinal serotonin- and norepinephrine-containing neurones that project to the spinal cord. This study investigates the involvement of spinal alpha(2)-adrenoceptors (α2-ARs) and 5-hydroxytryptamine (serotonin) receptors (5-HTRs) in EA effects on an inflammatory pain rat model. METHODS: Inflammatory hyperalgesia was induced by injecting complete Freund's adjuvant (CFA, 0.08 ml) into the plantar surface of one hind paw and assessed by paw withdrawal latency (PWL) to a noxious thermal stimulus. The selective α2a-AR antagonist BRL-44408, α2b-AR antagonist imiloxan hydrochloride, 5-HT2B receptor (5-HT2BR) antagonist SB204741, 5-HT3R antagonist LY278584, or 5-HT1AR antagonists NAN-190 hydrobromide, or WAY-100635 were intrathecally administered 20 min before EA or sham EA, which was given 2 h post-CFA at acupoint GB30. RESULTS: EA significantly increased PWL compared with sham [7.20 (0.46) vs 5.20 (0.43) s]. Pretreatment with α2a-AR [5.35 (0.45) s] or 5-HT1AR [5.22 (0.38) s] antagonists blocked EA-produced anti-hyperalgesia; α2b-AR, 5-HT2BR, and 5-HT3R antagonist pretreatment did not. Sham plus these antagonists did not significantly change PWL compared with sham plus vehicle, indicating that the antagonists had little effect on PWL. Immunohistochemical staining demonstrated that α2a-ARs are on primary afferents and 5-HT1ARs are localized in N-methyl-d-aspartic acid (NMDA) subunit NR1-containing neurones in the spinal dorsal horn. CONCLUSIONS: The data show that α2a-ARs and 5-HT1ARs are involved in the EA inhibition of inflammatory pain and that the NMDA receptors are involved in EA action.

Electroacupuncture alleviates affective pain in an inflammatory pain rat model.

Pain has both sensory-discriminative and emotional-affective dimensions. Previous studies demonstrate that electroacupuncture (EA) alleviates the sensory dimension but do not address the affective. An inflammatory pain rat model, produced by a complete Freund adjuvant (CFA) injection into the hind paw, was combined with a conditioned place avoidance (CPA) test to determine whether EA inhibits spontaneous pain-induced affective response and, if so, to study the possibility that rostral anterior cingulate cortex (rACC) opioids underlie this effect. Male Sprague-Dawley rats (250-275 g, Harlan) were used. The rats showed place aversion (i.e. affective pain) by spending less time in a pain-paired compartment after conditioning than during a preconditioning test. Systemic non-analgesic morphine (0.5 and 1.0 mg/kg, i.p.) inhibited the affective reaction, suggesting that the affective dimension is underpinned by mechanisms different from those of the sensory dimension of pain. Morphine at 0.5 and at 1 mg/kg did not induce reward. Rats given EA treatment before pain-paired conditioning at GB 30 showed no aversion to the pain-paired compartment, indicating that EA inhibited the affective dimension. EA treatment did not produce reward or aversive effect. Intra-rACC administration of D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr amide (CTOP), a selective mu opioid receptor antagonist, but not norbinaltorphimine (nor-BNI), a selective kappa opioid receptor antagonist, blocked EA inhibition of the affective dimension. These data demonstrate that EA activates opioid receptors in the rACC to inhibit pain-induced affective responses and that EA may be an effective therapy for both the sensory-discriminative and the affective dimensions of pain.

Interleukin 1beta facilitates bone cancer pain in rats by enhancing NMDA receptor NR-1 subunit phosphorylation.

It has been shown that interleukin-1beta (IL-1beta) facilitates nociception during neuropathic and inflammatory pain, but its involvement in bone cancer pain and its mechanisms have not previously been established. This study is an investigation of IL-1beta spinal expression and the N-methyl-D-aspartate (NMDA) receptor (NMDAR) NR1 subunit phosphorylation during cancer pain, co-localization of IL-1 receptor type I (IL-1RI) and NMDAR in the spinal cord, and the effects of IL-1 receptor antagonist (IL-1ra) on NMDAR1 (NR1) phosphorylation and hyperalgesia in a rat model of bone cancer pain. Cancer was induced by injecting AT-3.1 prostate cancer cells into the tibia of the male Copenhagen rat. Phosphorylation of NR1, an essential subunit of the NMDAR, is known to modulate NMDAR activity and facilitate pain. Mechanical hyperalgesia, established by a decrease in paw withdrawal pressure threshold (PWPT), was measured at baseline and 2 h after IL-1ra treatment. IL-1ra was given (i.t.) daily for 7 days between days 13 and 19 after the cancer cell inoculation. Spinal cords were removed for Western blot to measure IL-1beta and NR1 phosphorylation and for double immunostaining of IL-1RI and NR1. The data showed that 1) spinal IL-1beta was up-regulated and NR1 phosphorylation was increased, 2) IL-1ra at 0.1 mg/rat significantly (P<0.05) inhibited mechanical hyperalgesia, increasing PWPT on day 14 from 71.1+/-3.1-85.3+/-4.6 g and on day 19 from 73.5.0+/-3.5-87.1+/-3.7 g, and inhibited NR1 phosphorylation compared with saline control, and 3) IL-1RI is localized in NR1-immunoreactive neurons within the spinal cord. The results suggest that spinal IL-1beta enhances NR1 phosphorylation to facilitate bone cancer pain.

Effects of an acetone extract of Boswellia carterii Birdw. (Burseraceae) gum resin on adjuvant-induced arthritis in lewis rats.

Ruxiang (Gummi olibanum), the dried gum resin of Boswellia carterii (BC), has been used in traditional Chinese medicine to alleviate pain and inflammation for thousands of years. In this random, blinded study, the anti-arthritic effects of a BC extract were observed and compared to vehicle control in a Lewis rat adjuvant arthritis model (n=8/group). Arthritis was induced by injecting CFA subcutaneously into the base of the tail, and the extract was administered orally (i.g.) for 10 consecutive days beginning on day 16 after the injection. Arthritic scores, paw edema, and the local tissue pro-inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1beta) were assessed. Toxicity and adverse effects of the extract were evaluated. At 0.90 g/kg per day, BC significantly decreased arthritic scores between days 20 and 25 (p<0.05) and reduced paw edema on days 18, 20 and 22 compared to control (p<0.05). It also significantly suppressed local tissue TNF-alpha and IL-1beta (p<0.05). No major adverse effects were observed in animals during the repeated-dose treatment profile although mild fur discoloration was noted. The data show that BC extract has significant anti-arthritic and anti-inflammation effects and suggest that these effects may be mediated via the suppression of pro-inflammatory cytokines.

Acupuncture and dry-needling for low back pain.

BACKGROUND: Although low-back pain is usually a self-limiting and benign disease that tends to improve spontaneously over time, a large variety of therapeutic interventions are available for its treatment. OBJECTIVES: To assess the effects of acupuncture for the treatment of non-specific low-back pain and dry-needling for myofascial pain syndrome in the low-back region. SEARCH STRATEGY: We updated the searches from 1996 to February 2003 in CENTRAL, MEDLINE, and EMBASE. We also searched the Chinese Cochrane Centre database of clinical trials and Japanese databases to February 2003. SELECTION CRITERIA: Randomized trials of acupuncture (that involves needling) for adults with non-specific (sub)acute or chronic low-back pain, or dry-needling for myofascial pain syndrome in the low-back region. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed methodological quality (using the criteria recommended by the Cochrane Back Review Group) and extracted data. The trials were combined using meta-analyses methods or levels of evidence when the data reported did not allow statistical pooling. MAIN RESULTS: Thirty-five RCTs were included; 20 were published in English, seven in Japanese, five in Chinese and one each in Norwegian, Polish and German. There were only three trials of acupuncture for acute low-back pain. They did not justify firm conclusions, because of small sample sizes and low methodological quality of the studies. For chronic low-back pain there is evidence of pain relief and functional improvement for acupuncture, compared to no treatment or sham therapy. These effects were only observed immediately after the end of the sessions and at short-term follow-up. There is evidence that acupuncture, added to other conventional therapies, relieves pain and improves function better than the conventional therapies alone. However, effects are only small. Dry-needling appears to be a useful adjunct to other therapies for chronic low-back pain. No clear recommendations could be made about the most effective acupuncture technique. AUTHORS' CONCLUSIONS: The data do not allow firm conclusions about the effectiveness of acupuncture for acute low-back pain. For chronic low-back pain, acupuncture is more effective for pain relief and functional improvement than no treatment or sham treatment immediately after treatment and in the short-term only. Acupuncture is not more effective than other conventional and "alternative" treatments. The data suggest that acupuncture and dry-needling may be useful adjuncts to other therapies for chronic low-back pain. Because most of the studies were of lower methodological quality, there certainly is a further need for higher quality trials in this area.

The growth of health-related meta-analyses published from 1980 to 2000.

A MEDLINE search was conducted to estimate trends in the growth of health-related meta-analyses published during the past two decades. Employing a more specific than sensitive search strategy, and not supplementing these results with known sources of published meta-analyses or manual search strategies, 3,025 probable meta-analyses were selected from the 5,128 citations identified. The data showed a definitive upward (and generally linear) trend across time with no evidence for this genre of research either leveling off or decreasing.

Clinical decisions in the use of acupuncture as an adjunctive therapy for osteoarthritis of the knee.

OBJECTIVE: To determine whether demographic, medical history, or arthritis assessment data may influence outcome and rate of decay for patients with osteoarthritis treated with acupuncture. DESIGN: Seventy-three persons with symptomatic osteoarthritis of the knee were recruited for this randomized controlled trial. Both treatment and crossover control groups received acupuncture treatments twice weekly for 8 weeks. Patients self-scored on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the Lequesne Algofunctional Index at baseline and 4, 8, and 12 weeks. Sample size for this outcome analysis was 60 patients at 4 weeks, 58 at 8 weeks, and 52 at 12 weeks. RESULTS: Patients' scores on both indexes improved at 4, 8, and 12 weeks. Scores were stable regardless of the baseline severity of the osteoarthritis. Despite some decay in outcomes at week 12, measures were significantly improved over baseline. With WOMAC scores partitioned into equal quartiles, a strong effect on outcome was apparent at 12 weeks (4 weeks after treatment) related to initial WOMAC scores. The group with the least disability and pain rebounded to original levels to a greater degree than did those who initially were more disabled. The more disabled groups retained the benefits of acupuncture treatment through the 12-week period. CONCLUSION: Acupuncture for patients with osteoarthritis of the knee may best be used early in the treatment plan, with a methodical decrease in frequency in treatment once the acute treatment period is completed to avoid a rebound effect. Demographic and medical history data were not mediating variables.

La utilización de tratamientos no farmacológicos por los especialistas en dolor / The use of non-pharmacological treatments by pain specialist

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Demographic and health-related correlates to visits to complementary and alternative medical providers.

OBJECTIVES: The objective of this study was to ascertain the extent to which demographic and health-related variables are related to visits to a complementary or alternative medicine (CAM) practitioner. METHODS: This study reports a secondary analysis of visits to CAM practitioners during the year before the 1996 Medical Expenditure Panel Survey (n = 16,038). RESULTS: Overall visits to CAM providers (9%) were lower than reported in widely cited surveys but quite consistent with a previous Robert Wood Johnson study that used a similar sampling procedure. Gender, education, age, geographic location, and race (Hispanics and African Americans proved to be less likely to visit CAM providers than whites) were statistically significant predictors of visits to CAM providers. Individuals in poorer health and those suffering from mental, musculoskeletal, and metabolic disorders also tended to be more likely to have visited a CAM provider. CONCLUSIONS: Although the choice of alternative versus orthodox treatment appears to be a complex phenomenon, these data suggest that the heaviest users of CAM therapies tend to be individuals with comorbid, non-life-threatening health problems. This finding may help to ameliorate concerns that this type of care is being used in lieu of therapies with more definitive efficacy evidence.

Electro-acupuncture attenuates behavioral hyperalgesia and selectively reduces spinal Fos protein expression in rats with persistent inflammation.

This study examined the effect of electro-acupuncture (EA) on persistent inflammatory hyperalgesia in a rat model. Inflammation and hyperalgesia were induced by injecting complete Freund's adjuvant (CFA) into one hindpaw of the rat. Hyperalgesia was determined by a decrease in paw withdrawal latencies (PWL) to a noxious thermal stimulus. EA was applied bilaterally at the acupuncture point Huantiao (G30) at the rat's hindlimbs. EA-treated rats (n = 11) had significantly longer PWLs as compared with placebo control rats (n = 7) in the inflamed paw at 2.5 hours and 5 days after injection of CFA (P <.05) and longer PWLs as compared to sham control rats (n = 9) at 2.5 hours (P >.05). Paw edema was significantly reduced in EA-treated rats versus placebo controls at 24 hours after inflammation (P <.01). Inflammation-induced spinal Fos expression in the medial half of laminae I-II in EA-treated rats versus placebo rats (n = 5 per group) was significantly reduced (P <.01). These data showed that EA delayed the onset and facilitated the recovery of inflammatory hyperalgesia and suppressed the inflammation-induced spinal Fos expression in neurons (laminae I-II) involved in receiving noxious stimulation. This rat model of persistent pain and inflammation seems to be an ideal animal model for studying the effect of acupuncture.

Clinical applications of acupuncture: an overview of the evidence.

This presentation provides an overview of studies that are of sound methodological quality and that contribute to the understanding of acupuncture. It is difficult to design an appropriate control group for acupuncture because acupuncture is an invasive, physical modality. No single control group can answer all of the research questions. Therefore, many types of control groups, each with advantages and disadvantages, have been used, depending on the specific questions being asked. Examples are taken from the different categories of control groups (e.g., acupuncture versus standard medical care). A model for future acupuncture research, which is simultaneously comprehensive and cost effective, is described.

Seminal studies in acupuncture research.

Acupuncture, a component of the health care system of China that can be traced back at least 2500 years, describes a family of procedures involving stimulation of anatomical locations on the skin by a variety of techniques. In November 1997, the National Institutes of Health conducted a consensus conference during which a panel of experts convened to discuss the scientific evidence regarding acupuncture. The panel concluded that acupuncture is an effective treatment for several medical conditions and described biochemical and physiologic mechanisms that begin to explain these effects. This presentation summarizes the evidence of the clinical efficacy of acupuncture and is divided into three segments. The first segment presents an overview of evidence-based medicine, the second segment summarizes the current evidence from systematic reviews of acupuncture, and the third segment looks to the future by proposing a stepwise method for designing phase I, II, and III acupuncture clinical trials.

Mind-body therapies for the treatment of fibromyalgia. A systematic review.

OBJECTIVE: To assess the effectiveness of mind-body therapy (MBT) for fibromyalgia syndrome (FM) by systematically reviewing randomized/quasirandomized controlled trials using methods recommended by the Cochrane Collaboration. METHODS: Nine electronic databases, 69 conference proceedings, and several citation lists were searched for relevant trials in any language. Eligible trials were scored for methodological quality using a validated instrument. Information on major outcomes was extracted. Insufficient data reporting prevented statistical pooling, therefore a best-evidence synthesis was performed. RESULTS: Thirteen trials involving 802 subjects were included. Seven trials received a high methodological score. Compared to waiting list/treatment as usual, there is strong evidence that MBT is more effective for self-efficacy, limited evidence for quality of life, inconclusive evidence for all other outcomes. There is limited evidence that MBT is more effective than placebo (for pain and global improvement); inconclusive evidence that MBT is more effective than physiotherapy, psychotherapy, or education/attention control for all outcomes; strong evidence that moderate/high intensity exercise is more effective than MBT (for pain and function). There is moderate evidence that MBT plus exercise (MBT+E) is more effective than waiting list/treatment as usual (for self-efficacy and quality of life); limited evidence that MBT+E is more effective than education/attention control; inconclusive for other outcomes. There is inconclusive evidence for MBT+E vs other active treatments for all outcomes. Longterm within-groups results show greatest benefit for MBT+E. CONCLUSION: MBT is more effective for some clinical outcomes compared to waiting list/treatment as usual or placebo. Compared to active treatments, results are largely inconclusive, except for moderate/high intensity exercise, where results favor the latter. Further research needs to focus on the synergistic effects of MBT plus exercise and/or plus antidepressants.

Osteoarthritis: new insights. Part 2: treatment approaches.

Osteoarthritis is the most common form of arthritis, affecting millions of people in the United States. It is a complex disease whose etiology bridges biomechanics and biochemistry. Evidence is growing for the role of systemic factors, such as genetics, diet, estrogen use, and bone density, and local biomechanical factors, such as muscle weakness, obesity, and joint laxity. These risk factors are particularly important in the weight-bearing joints, and modifying them may help prevent osteoarthritis-related pain and disability. Major advances in management to reduce pain and disability are yielding a panoply of available treatments ranging from nutriceuticals to chondrocyte transplantation, new oral anti-inflammatory medications, and health education. This article is part 2 of a two-part summary of a National Institutes of Health conference that brought together experts in osteoarthritis from diverse backgrounds and provided a multidisciplinary and comprehensive summary of recent advances in the prevention of osteoarthritis onset, progression, and disability. Part 2 focuses on treatment approaches; evidence for the efficacy of commonly used oral therapies is reviewed and information on alternative therapies, including nutriceuticals and acupuncture, is presented. Biomechanical interventions, such as exercise and bracing, and behavioral interventions directed toward enhancing self-management are reviewed. Current surgical approaches are described and probable future biotechnology-oriented approaches to treatment are suggested.

CAM evaluation comes into the mainstream: NIH specialized Centers of research and the University of Maryland Center for Alternative Medicine Research in Arthritis.

In September of 1999 the National Institutes of Health (NIH) announced the funding of five Specialized Centers of Research in complementary and alternative medicine (CAM), bringing the total number of centers being supported to nine. The NIH center grant model provides a tremendous boost to the scientific investigation of CAM, nurturing an emerging field through the support of a step-wise research program of clinical and pre-clinical trials and developmental and feasibility studies; the building of infrastructure; and the training of a new cadre of scientific investigators in the field. This article explains the overall objectives of the NIH Specialized Centers program and focuses on one of the oldest CAM research centers in the USA, exploring some of the challenges faced in conducting CAM research while developing a center, and some of the goals and activities of the center.

The evidence for acupuncture as a treatment for rheumatologic conditions.

Individuals with rheumatic disorders, particularly those with more severe, chronic conditions, are likely to be frequent users of complementary and alternative medical therapies. Although large-scale clinical trials have yet to be conducted, there is moderately strong evidence that acupuncture may be effective for treating both osteoarthritis and fibromyalgia. The utility of acupuncture in treating rheumatoid arthritis has not been demonstrated in large, randomized controlled trials. Physicians who treat patients with rheumatic conditions should become knowledgeable about the literature on both the effectiveness of acupuncture for these conditions as well as its potential to cause adverse side effects in particular patient groups.