Can the chronic administration of the combination of buprenorphine and naloxone block dopaminergic activity causing anti-reward and relapse potential?

Opiate addiction is associated with many adverse health and social harms, fatal overdose, infectious disease transmission, elevated health care costs, public disorder, and crime. Although community-based addiction treatment programs continue to reduce the harms of opiate addiction with narcotic substitution therapy such as methadone maintenance, there remains a need to find a substance that not only blocks opiate-type receptors (mu, delta, etc.) but also provides agonistic activity; hence, the impetus arose for the development of a combination of narcotic antagonism and mu receptor agonist therapy. After three decades of extensive research, the federal Drug Abuse Treatment Act 2000 (DATA) opened a window of opportunity for patients with addiction disorders by providing increased access to options for treatment. DATA allows physicians who complete a brief specialty-training course to become certified to prescribe buprenorphine and buprenorphine/naloxone (Subutex, Suboxone) for treatment of patients with opioid dependence. Clinical studies indicate that buprenorphine maintenance is as effective as methadone maintenance in retaining patients in substance abuse treatment and in reducing illicit opioid use. With that stated, we must consider the long-term benefits or potential toxicity attributed to Subutex or Suboxone. We describe a mechanism whereby chronic blockade of opiate receptors, in spite of only partial opiate agonist action, may ultimately block dopaminergic activity causing anti-reward and relapse potential. While the direct comparison is not as yet available, toxicity to buprenorphine can be found in the scientific literature. In considering our cautionary note in this commentary, we are cognizant that, to date, this is what we have available, and until such a time when the real magic bullet is discovered, we will have to endure. However, more than anything else this commentary should at least encourage the development of thoughtful new strategies to target the specific brain regions responsible for relapse prevention.

Healing enhancement of chronic venous stasis ulcers utilizing H-WAVE(R) device therapy: a case series.

INTRODUCTION: Approximately 15% (more than 2 million individuals, based on these estimates) of all people with diabetes will develop a lower-extremity ulcer during the course of the disease. Ultimately, between 14% and 20% of patients with lower-extremity diabetic ulcers will require amputation of the affected limb. Analysis of the 1995 Medicare claims revealed that lower-extremity ulcer care accounted for $1.45 billion in Medicare costs. Therapies that promote rapid and complete healing and reduce the need for expensive surgical procedures would impact these costs substantially. One such example is the electrotherapeutic modality utilizing the H-Wave(R) device therapy and program.It has been recently shown in acute animal experiments that the H-Wave(R) device stimulation induces a nitric oxide-dependent increase in microcirculation of the rat Cremaster skeletal muscle. Moreover, chronic H-wave(R) device stimulation of rat hind limbs not only increases blood flow but induces measured angiogenesis. Coupling these findings strongly suggests that H-Wave(R) device stimulation promotes rapid and complete healing without need of expensive surgical procedures. CASE PRESENTATION: We decided to do a preliminary evaluation of the H-Wave(R) device therapy and program in three seriously afflicted diabetic patients. Patient 1 had chronic venous stasis for 6 years. Patient 2 had chronic recurrent leg ulcerations. Patient 3 had a chronic venous stasis ulcer for 2 years. All were dispensed a home H-Wave(R) unit. Patient 1 had no other treatment, patient 2 had H-Wave(R) therapy along with traditional compressive therapy, and patient 3 had no other therapy.For patient 1, following treatment the ulcer completely healed with the H-Wave(R) device and program after 3 months. For patient 2, by one month complete ulcer closure occurred. Patient 3 had a completely healed ulcer after 9 months. CONCLUSIONS: While most diabetic ulcers can be treated successfully on an outpatient basis, a significant proportion will persist and become infected. Based on this preliminary case series investigation we found that three patients prescribed H-Wave(R) home treatment demonstrate accelerated healing with excellent results. While these results are encouraging, additional large scale investigation is warranted before any interpretation is given to these interesting outcomes.

Do dopaminergic gene polymorphisms affect mesolimbic reward activation of music listening response? Therapeutic impact on Reward Deficiency Syndrome (RDS).

Using fMRI, Menon and Levitin [9] clearly found for the first time that listening to music strongly modulates activity in a network of mesolimbic structures involved in reward processing including the nucleus accumbens (NAc) and the ventral tegmental area (VTA), as well as the hypothalamus, and insula, which are thought to be involved in regulating autonomic and physiological responses to rewarding and emotional stimuli. Importantly, responses in the NAc and VTA were strongly correlated pointing to an association between dopamine release and NAc response to music. Listing to pleasant music induced a strong response and significant activation of the VTA-mediated interaction of the NAc with the hypothalamus, insula, and orbitofrontal cortex. Blum et al. [10] provided the first evidence that the dopamine D2 receptor gene (DRD2) Taq 1 A1 allele significantly associated with severe alcoholism whereby the author's suggested that they found the first "reward gene" located in the mesolimbic system. The enhanced functional and effective connectivity between brain regions mediating reward, autonomic, and cognitive processing provides insight into understanding why listening to music is one of the most rewarding and pleasurable human experiences. However, little is known about why some people have a more or less powerful mesolimbic experience when they are listening to music. It is well-known that music may induce an endorphinergic response that is blocked by naloxone, a known opioid antagonist (Goldstein [19]). Opioid transmission in the NAc is associated with dopamine release in the VTA. Moreover, dopamine release in the VTA is linked to polymorphisms of the DRD2 gene and even attention-deficit hyperactivity disorder (ADHD), whereby carriers of the DRD2 A1 allele show a reduced NAc release of dopamine (DA). Thus it is conjectured that similar mechanisms in terms of adequate dopamine release and subsequent activation of reward circuitry by listening to music might also be affected by an individual's D2 density in the VTA mediated interaction of the NAc. It is therefore hypothesized that carriers of DRD2 A1 allele may respond significantly differently to carriers of the DRD2 A2 genotype. In this regard, carriers of the D2 A1 allele have a blunted response to glucose and monetary rewards. In contrast powerful D2 agonists like bromocryptine show a heightened activation of the reward circuitry only in DRD2 A1 allele carriers. If music causes a powerful activation in spite of the DRD2 A1 allele due to a strong DA neuronal release which subsequently impinges on existing D2 receptors, then it is reasonable to assume that music is a strong indirect D2 agonist (by virtue of DA neuronal release in the NAc) and may have important therapeutic applicability in Reward Deficiency Syndrome (RDS) related behaviors including Substance Use Disorder (SUD). Ross et al. [18] found that music therapy appears to be a novel motivational tool in a severely impaired inpatient sample of patients with co-occurring mental illness and addiction.

Repetitive H-wave device stimulation and program induces significant increases in the range of motion of post operative rotator cuff reconstruction in a double-blinded randomized placebo controlled human study.

BACKGROUND: Albeit other prospective randomized controlled clinical trials on H-Wave device stimulation (HWDS), this is the first randomized double-blind placebo controlled prospective study that assessed the effects of HWDS on range of motion and strength testing in patients who underwent rotator cuff reconstruction. METHODS: Twenty-two patients were randomly assigned into one of two groups: 1) H-Wave device stimulation (HWDS); 2) sham-placebo device (PLACEBO). All groups received the same postoperative dressing and the same device treatment instructions. Group I was given HWDS which they were to utilize for one hour twice a day for 90 days postoperatively. Group II was given the same instructions with a Placebo device (PLACEBO). Range of motion was assessed by using one-way ANOVA with a Duncan Multiple Range Test for differences between the groups preoperatively, 45 days postoperatively, and 90 days postoperatively by using an active/passive scale for five basic ranges of motions: Forward Elevation, External Rotation (arm at side), External Rotation (arm at 90 degrees abduction), Internal Rotation (arm at side), and Internal Rotation (arm at 90 degrees abduction). The study also evaluated postoperative changes in strength by using the Medical Research Council (MRC) grade assessed strength testing. RESULTS: Patients who received HWDS compared to PLACEBO demonstrated, on average, significantly improved range of motion. Results confirm a significant difference for external rotation at 45 and 90 days postoperatively; active range at 45 days postoperatively (p = 0.007), active at 90 days postoperatively (p = 0.007). Internal rotation also demonstrated significant improvement compared to PLACEBO at 45 and 90 days postoperatively; active range at 45 days postoperatively (p = 0.007), and active range at 90 days postoperatively (p = 0.006). There was no significant difference between the two groups for strength testing. CONCLUSION: HWDS compared to PLACEBO induces a significant increase in range of motion in positive management of rotator cuff reconstruction, supporting other previous research on HWDS and improvement in function. Interpretation of this preliminary investigation while suggestive of significant increases in Range of Motion of Post -Operative Rotator Cuff Reconstruction, warrants further confirmation in a larger double-blinded sham controlled randomized study.

LG839: anti-obesity effects and polymorphic gene correlates of reward deficiency syndrome.

INTRODUCTION: This study systematically assessed the weight management effects of a novel experimental DNA-customized nutraceutical, LG839 (LifeGen, Inc., La Jolla, CA, USA). METHODS: A total of 1058 subjects who participated in the overall D.I.E.T. study were genotyped and administered an LG839 variant based on polymorphic outcomes. A subset of 27 self-identified obese subjects of Dutch descent, having the same DNA pattern of four out of the five candidate genes tested (chi-square analysis) as the entire data set, was subsequently evaluated. Simple t tests comparing a number of weight management parameters before and after 80 days of treatment with LG839 were performed. RESULTS: Significant results were observed for weight loss, sugar craving reduction, appetite suppression, snack reduction, reduction of late night eating (all P<0.01), increased perception of overeating, enhanced quality of sleep, increased happiness (all P<0.05), and increased energy (P<0.001). Polymorphic correlates were obtained for a number of genes (LEP, PPAR-gamma2, MTHFR, 5-HT2A, and DRD2 genes) with positive clinical parameters tested in this study. Of all the outcomes and gene polymorphisms, only the DRD2 gene polymorphism (A1 allele) had a significant Pearson correlation with days on treatment (r=0.42, P=0.045). CONCLUSION: If these results are confirmed in additional rigorous, controlled studies, we carefully suggest that DNA-directed targeting of certain regulator genes, along with customized nutraceutical intervention, provides a unique framework and strategic modality to combat obesity.

The H-Wave device is an effective and safe non-pharmacological analgesic for chronic pain: a meta-analysis.

INTRODUCTION: This meta-analysis was conducted to systematically review the efficacy and safety of the H-Wave (Electronic Waveform Lab, Inc, Huntington Beach, CA, USA) device and programme as a non-pharmacological analgesic treatment in chronic soft tissue inflammation and neuropathic pain. METHODS: Five studies related to pain relief, reduction in pain medication and increased functionality obtained with the H-Wave device were included in the analysis. Data were analysed using the random effects model, including adjustment to evaluate variability, size of study and bias in effect size. A total of 6535 participants were included in the meta-analysis; there were 8065 participants' outcomes measured due to multiple measurements per participant. RESULTS: The H-Wave device decreased pain ratings across various chronic soft tissue inflammation and neuropathic pain conditions. The mean weighted effect size was 0.59, and the estimated effect size variance was 0.00003 (95% confidence intervals [CI]: 0.580, 0.600). The H-Wave device also decreased the intake of pain medication in patients with various chronic soft tissue inflammation and neuropathic pain conditions. The mean weighted effect size was 0.56, and the estimated effect size variance was 0.000013 (95% CI: 0.553, 0.567). Patient functionality was also improved with use of the H-Wave device. The mean weighted effect size was 0.70, and the estimated effect size variance was 0.00002 (95% CI: 0.691, 0.709). A chi-square test for homogeneous effect sizes found highly significant (P<0.00001) variability, indicating a robust significant effect size for increased functionality relative to both pain relief and reduction in pain medication. There was little to no evidence of any adverse effects associated with the use of the H-Wave device. CONCLUSION: The findings indicate a moderate to strong effect of the H-Wave device in providing pain relief, reducing the requirement for pain medication and increasing functionality. The most robust effect was observed for improved functionality, suggesting that the H-Wave device may facilitate a quicker return to work and other related daily activities.