Health  Vol.5 No.11 A , November 2013
Iatrogenic opioid dependence is endemic and legal: Genetic addiction risk score (GARS) with electrotherapy a paradigm shift in pain treatment programs
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Abstract: The mounting endemic of prescription iatrogenic opioid dependence in pain patients provoked this treatise about an alternative method that can be used to treat pain, improve function and reduce the risk of opioid dependence. It is well known that as well as the side effects reported for chronic opioid therapy, genetically predisposed individuals are at risk for opioid dependence. We propose the use of the Genetic Addiction Risk Score (GARS) assessment to identify patients early in treatment who should avoid narcotic pain medications. Primarily, this review will be an exploration of the mechanisms of action of an electrotherapeutic alternative to narcotic treatment that can be used to augment tissue healing and reduce the pain associated with human injuries and neuropathies. This particular electrotherapeutic device was developed at the Electronic Waveform Laboratory in Huntington Beach, California and is called the H-Wave? device. The primary effect of the H-Wave?device is stimulation (HWDS) of small diameter fibers of “red-slow-twitch” skeletal muscle. Mechanisms of action of HWDS have been investigated in both animal and human studies. They include edema reduction, induction of nitric oxide dependent augmented microcirculation and angiogenesis, small muscle contraction that eliminates transcapillary fluid shifts, reducing the painful effects of tetanizing fatigue and gradual loading of healing injured muscle tissue that helps repair and remodeling. A recent metaanalysis found a moderate-to-strong-positive effect of the HWDS in providing pain relief, reducing the requirement for pain medication, with the most robust effect being increased functionality. We are proposing that GARS can be used to identify those at risk of developing opioid dependence and that the need for opioid analgesia can be reduced by use of this electro therapeutic alternative to opioid analgesia in the treatment of pain and injuries.
Cite this paper: Blum, K. , Han, D. , Oscar-Berman, M. , Reinl, G. , DiNubile, N. , Madigan, M. , Bajaj, A. , Downs, B. , Giordano, J. , Westcott, W. , Smith, L. , Braverman, E. , Dushaj, K. , Hauser, M. , Simpatico, T. , McLaughlin, T. , Borsten, J. and Barh, D. (2013) Iatrogenic opioid dependence is endemic and legal: Genetic addiction risk score (GARS) with electrotherapy a paradigm shift in pain treatment programs. Health, 5, 16-34. doi: 10.4236/health.2013.511A1004.

[1]   CDC grand rounds: Prescription drug overdose—A US epidemic. (2012) 10-13.

[2]   Dunn, K.M., Saunders, K.W., Rutter, C.M., Banta-Green, C.J., Merrill, J.O., Sullivan, M.D., Weisner, C.M. Michael J. Silverberg, M.J., Campbell, C.I., Psaty, B.M. and Von Korff, M. (2010) Opioid prescriptions for chronic pain and overdose. Annals of Internal Medicine, 152, 85-92.

[3]   Boudreau, D., Von Korff, M., Rutter, C.M., Saunders, K., G. Thomas Ray, T., Sullivan, M.D., Campbell, C., Merrill, J.O., Silverberg, M.J., Banta-Green, C. and Weisner, C. (2009) Trends in long-term opioid therapy for chronic non-cancer pain. Pharmacoepidemiology and Drug Safety, 18, 1166-1175.

[4]   Substance Abuse and Mental Health Services Administration (2010) Results from the 2009 national survey on drug use and health: Volume 1: Summary of national findings. Substance Abuse and Mental Health Services Administration, Rockville.

[5]   Edlund, M.J., Martin, B.C., Fan, M.Y., Braden, J.B., Devries, A. and Sullivan, M.D. (2010) An analysis of heavy utilizers of opioids for chronic noncancer pain in the TROUP Study. Journal of Pain and Symptom Management, 40, 279-289.

[6]   Katz, N., Panas, L., Kim, M., Audet, A.D., Bilansky, A., Eadie, J., Kreiner, P., Paillard, F.C., Thomas, C. and Carrow, G. (2010) Usefulness of prescription monitoring programs for surveillance—Analysis of schedule II opioid prescription data in Massachusetts, 1996-2006. Pharmacoepidemiology and Drug Safety, 19, 115-123.

[7]   Bohnert, A.S., Valenstein, M., Bair, M.J., Ganoczy, D., McCarthy, J. F., Ilegen, M. A. and Blow, F.C. (2011) Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA, 305, 1315-1321.

[8]   Hall, A.J., Logan, J.E., Toblin, R.L., Kaplan, J.A., Kraner, J.C., Bixler, D., Crosby, A.E. and Paulozzi, L.J. (2008) Patterns of abuse among unintentional pharmaceutical overdose fatalities. JAMA, 300, 2613-2620.

[9]   Kumar, K., Taylor, R.S., Jacques, L., Eldabe, S., Meglio, M., Molet, J., Thomson, S., O’Callaghan, J., Eisenberg, E., Milbouw, G., Buchser, E., Fortini, G., Richardson, J. and North, R.B. (2007) Spinal cord stimulation versus conventional medical management for neuropathic pain: A multicentre randomized trial in patients with failed back surgery syndrome. Pain, 132, 179-188.

[10]   Blum, K., Chen, T.J. and Ross, B.D. (2005) Innate properties of H-wave device, a small fiber stimulator provides the basis for a paradigm shift of electro-therapeutic treatment of pain with increased functional restoration associated with human neuropathies by affecting tissue circulation: A hypothesis. Medical Hypotheses, 64, 1066-1067.

[11]   Blum, K., Ho, C.K., Chen, L.C., Fulton, M., Fulton, B., Westcott, W., Reinl, G., Braverman, E.R., Dinubile, N. and Chen, T.J.H. (2008) The H-wave device induces NO—Dependent augmented microcirculation and angiogenesis, providing both analgesia and tissue healing in sports injuries. The Physician Sports Medicine, 36, 103-114.

[12]   Smith, T.L., Blum, K., Callahan, M.F., Di Nubile, N.A., Chen, T.J. and Waite, R.L. (2009) H-wave induces arteriolar vasodilation in rat striated muscle via Nitric Oxide-mediated mechanisms. Journal of Orthopaedic Research, 27, 1248-1251.

[13]   Smith, T.L., Blum, K., Waite, R.L., Heaney, W.J. and Callahan, M. (2007) The microvascular and hemodynamic mechanisms for the therapeutic actions of H-wave muscle stimulation. The 6th Combined Meeting of the Orthopaedic Research Societies, 21 October 2007, Honolulu.

[14]   Kumar, D. and Marshall, H.J. (1997) Diabetic peripheral neuropathy: Amelioration of pain with transcutaneous electrostimulation. Diabetes Care, 20, 1702-1705.

[15]   Kumar, D., Alvaro, M.S. and Julka, I.S. (1998) Marshall HJ: Diabetic peripheral neuropathy: Effectiveness of electrotherapy and amitriptyline for symptomatic relief. Diabetes Care, 21, 1322-1325.

[16]   Julka, I.S., Alvaro, M. and Kumar, D. (1998) Beneficial effects of electrical stimulation on neuropathic symptoms in diabetes patients. Journal of Foot and Ankle Surgery, 37, 191-194.

[17]   Blum, K., Dinublie, N., Chen, T.J.H., Waite, R.L., Martinez-Pons, M., Callahan, M.F., Smith, T.L., Mengucci, J., Blum, S.H. and Meshkin, B. (2006) H-wave, a nonpharmacologic alternative for the treatment of patients with chronic soft tissue inflammation and neuropathic pain: A preliminary statistical outcome study. Advances in Therapy, 23, 446-455.

[18]   Blum, K., Martinez-Pons, M., Dinubile, N.A., Waite, R.L., Schoolfield, J., Blum, S.H., Mengucci, J., Downs, B.W. and Meshkin, B, (2006) H-Wave device, a small muscle fiber stimulator, significantly reduces pain medication, increases function and improves health in 6774 patients with chronic soft tissue injuries and/or neuropathic pain: An extended population observational study. Advances in Therapy, 23, 739-749.

[19]   Blum, K., Chen, A.L., Chen, T.J., Prihoda, T.J., Schoolfield, J., Dinubile, N., Waite, R.L., Arcuri. V., Kerner, M., Braverman, E.R., Rhoades, P. and Tung, H. (2008) The H-wave® device is an effective and safe non-pharmacological analgesic for chronic pain: A meta-analysis. Advances in Therapy, 25, 644-657.

[20]   Blum, K., Chen, J.H.T. and Ross, B.D. (2005) Innate properties of H-wave device, a small fiber stimulator provides the basis for a paradigm shift of electro-therapeutic treatment of pain with increased functional restoration associated with human neuropathies. Townsend Letter for Doctors and Patients, 1, 101-104.

[21]   Blum, K., Chen, A.L., Chen, T.J., Waite, R.L., Downs, B.W., Braverman, E.R., Kerner, M.M., Savarimuthu, S.M. and DiNubile, N. (2009) 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. BMC Musculoskeletal Disorders, 10, 132.

[22]   Blum, K., Chen, A.L.H., Chen, T.J.H., Downs, B.W., Braverman, E.R., Kerner, M., Savraimuthu, S., Madigan, M., Blum, S.H., Reinl, G. and Dinubile, N. (2010) Healing enhancement of chronic venous stasis ulcers utilizing H-wave® device therapy: A case series. BMC—Cases Journal, 3, 54.

[23]   Smith, T.I., Callahan, M.F., Blum, K., DiNubile, N., Chen, T.J.H. and Waite, R.L. (2011) H-wave® effects on blood flow and angiogenesis in longitudinal studies in rats. Journal of Surgical Orthopaedic Advances, 20, 255-259.

[24]   Blum, K., Ho, C.K., Chen, A.L., Fulton, M., Fulton, B., Westcott, W.L., Reinl, G., Braverman, E.R., Dinubile, N. and Chen, T.J. (2008) The H-wave®device induces NO dependent augmented microcirculation and angiogenesis, providing both analgesia and tissue healing in sports injuries. Physician and Sportsmedicine, 36, 103-114.

[25]   Tsang, B.K., Tajkaushi, K. and Eichhorn, J.H. (1998) Electrical stimulation reduces symptoms of thermal hypersensitivity from injury of sciatic partial ligation in rats. Anesthesia & Analgesia, 86, S1-S551.

[26]   Flatt, D.W. (1994) Resolution of a double crush syndrome. Journal of Manipulative and Physiological Therapeutics, 17, 395-397.

[27]   Mak, A.F., Yu, Y., Kwan, L.P., Sun, L. and Tam, E.W. (2011) Deformation and reperfusion damages and their accumulation in subcutaneous tissues during loading and unloading: A theoretical modeling of deep tissue injuries. Journal of Theoretical Biology, 289, 65-73.

[28]   Szczesny, S.E., Lee, C.S. and Soslowsky, L.J. (2010) Remodeling and repair of orthopedic tissue: Role of mechanical loading and biologics. The American Journal of Orthopedics, 39, 525-530.

[29]   Buckwalter, J.A. and Grodzinsky, A.J. (1999) Loading of healing bone, fibrous tissue, and muscle: Implications for orthopedic practice. Journal of the American Academy of Orthopaedic Surgeons, 7, 291-299.

[30]   Gray, M.L., Pizzanelli, A.M., Grodzinsky, A.J. and Lee, R.C. (1988) Mechanical and physicochemical determinants of the chondrocyte biosynthetic response. Journal of Orthopaedic Research, 6, 777-792.

[31]   Grodzinsky, A.J. (1983) Electromechanical and physicochemical properties of connective tissue. Critical ReviewsTM in Biomedical Engineering, 9, 133-199.

[32]   Ingber, D.E. (1997) Tensegrity: The architectural basis of cellular mechanotransduction. Annual Review of Physiology, 59, 575-599.

[33]   Toma, C.D., Ashkar, S., Gray, M.L., Schaffer, J.L. and Gerstenfeld, L.C. (1997) Signal transduction of mechanical stimuli is dependent on microfilament integrity: Identification of osteopontin as a mechanically induced gene in osteoblasts. Journal of Bone and Mineral Research, 12, 1626-1636.

[34]   Guilak, F. (1995) Compression-induced changes in the shape and volume of the chondrocyte nucleus. Journal of Biomechanics, 28, 1529-1541.

[35]   Kim, Y.J., Grodzinsky, A.J. and Plaas, A.H. (1996) Compression of cartilage results in differential effects on biosynthetic pathways for aggrecan, link protein and hyaluronan. Archives of Biochemistry and Biophysics, 328, 331-340.

[36]   Buschmann, M.D., Gluzband, Y.A., Grodzinsky, A.J. and Hunziker, E.B. (1995) Mechanical compression modulates matrix biosynthesis in chondrocyte/agarose culture. Journal of Cell Science, 108, 1497-1508.

[37]   Quinn, T.M., Grodzinsky, A.J., Buschmann, M.D., Kim, Y.J. and Hunziker, E.B. (1998) Mechanical compression alters proteoglycan deposition and matrix deformation around individual cells in cartilage explants. Journal of Cell Science, 111, 573-583.

[38]   Chen, C.S. and Ingber, D.E. (1999) Tensegrity and mechanoregulation: From skeleton to cytoskeleton. Osteoarthritis and Cartilage, 7, 81-94.

[39]   Smalt, R., Mitchell. F.T., Howard, R.L. and Chambers, T.J. (1997) Mechanotransduction in bone cells: Induction of nitric oxide and prostaglandin synthesis by fluid shear stress, but not by mechanical strain. Advances in Experimental Medicine and Biology, 433, 311-314.

[40]   Eliasson, P., Andersson, T. and Aspenberg, P. (2009) Rat Achilles tendon healing: Mechanical loading and gene expression. Journal of Applied Physiology, 107, 399-407.

[41]   Andersson, T., Eliasson, P. and Aspenberg, P. (2009) Tissue memory in healing tendons: Short loading episodes stimulate healing. Journal of Applied Physiology, 107, 417-421.

[42]   Nachemson, A. (1985) Recent advances in the treatment of low back pain. International Orthopaedics, 9, 1-10.

[43]   Nachemson, A. (1975) Towards a better understanding of low-back pain: A review of the mechanics of the lumbar disc. Rheumatology and Rehabilitation, 14, 129-143.

[44]   Owan, I., Burr, D.B., Turner, C.H., Qiu, J., Tu, Y., Onyia, J.E. and Duncan, R.L. (1997) Mechanotransduction in bone: Osteoblasts are more responsive to fluid forces than mechanical strain. The American Journal of Physiology, 273, C810-C815.

[45]   Sah, R.L., Kim, Y.J., Doong, J.Y., Grodzinsky, A.J., Plaas, A.H., Sandy, J.D. (1989) Biosynthetic response of cartilage explants to dynamic compression. Journal of Orthopaedic Research, 7, 619-636.

[46]   Garcia, A.M., Frank, E.H., Grimshaw, P.E. and Grodzinsky, A.J. (1996) Contributions of fluid convection and electrical migration to transport in cartilage: Relevance to loading. Archives of Biochemistry Biophysics, 333, 317-325.

[47]   Buckwalter, J.A. (1995) Should bone, soft-tissue, and joint injuries be treated with rest or activity? Journal of Orthopaedic Research, 13, 155-156.

[48]   Caplan, A., Carlson, B., Faulkner, J., Fischman, D. and Garrett Jr., W. (1988) Skeletal muscle. In: Woo, S.L.Y. and Buckwalter, J.A., Eds., Injury and Repair of the Musculoskeletal Soft Tissues, American Academy of Orthopaedic Surgeons, Park Ridge, 213-291.

[49]   Buckwalter, J.A., Woo, S.L.Y. and Goldberg, V.M. (1993) Soft-tissue aging and musculoskeletal function. The Journal of Bone and Joint Surgery, American Volume, 75, 1533-1548.

[50]   National Institutes of Arthritis and Musculoskeletal and Skin Diseases, (2009).

[51]   Uhthoff, H.K. and Jaworski, Z.F. (1978) Bone loss in response to long-term immobilisation. The Journal of Bone and Joint Surgery. British Volume, 60, 420-429.

[52]   Burr, D.B., Frederickson, R.G., Pavlinch, C., Sickles, M. and Burkart, S. (1984) Intracast muscle stimulation prevents bone and cartilage deterioration in cast-immobilized rabbits. Clinical Orthopaedics and Related Research, 189, 264-278.

[53]   Jordan, K.M. and Cooper, C. (2002) Epidemiology of osteoporosis. Best Practice & Research Clinical Rheumatology, 16, 795-806.

[54]   Gennari, L., Merlotti, D., De Paola, V., Martini, G., Nuti, R. (2009) Update on the pharmacogenetics of the vitamin D receptor and osteoporosis. Pharmacogenomics, 10, 417-433.

[55]   McClung, J.P. and Karl, J.P. (2010) Vitamin D and stress fracture: The contribution of vitamin D receptor gene polymorphisms. Nutrition Reviews, 68, 365-369.

[56]   Goodship, A.E., Lanyon, L.E. and McFie, H. (1979) Functional adaptation of bone to increased stress: An experimental study. The Journal of Bone and Joint Surgery. American Volume, 61, 539-546.

[57]   Alvarez-Hernandez, D., Naves-Diaz, M., Gomez-Alonso, C., Coto, E. and Cannata-Andia, J.B. (2008) Tissue-specific effect of VDR gene polymorphisms on the response to calcitriol. Journal of Nephrology, 21, 843-849.

[58]   Hou, X., Weiler, M.A., Winger, J.N., Morris, J.R. and Borke, J.L. (2009) Rat model for studying tissue changes induced by the mechanical environment surrounding loaded titanium implants. The International Journal of Oral & Maxillofacial Implants, 24, 800-807.

[59]   Akeson, W.H., Woo, S.L.Y., Amiel, D., Coutts, R.D. and Daniel, D. (1973) The connective tissue response to immobility: Biochemical changes in periarticular connective tissue of the immobilized rabbit knee. Clinical Orthopaedics and Related Research, 93, 356-362.

[60]   Noyes, F.R., DeLucas, J.L. and Torvik, P.J. (1974) Biomechanics of anterior cruciate ligament failure: An analysis of stain-rate sensitivity and mechanisms of failure in primates. The Journal of Bone and Joint Surgery, 56, 236-253.

[61]   Laros, G.S., Tipton, C.M. and Cooper, R.R. (1971) Influence of physical activity on ligament insertions in the knees of dogs. The Journal of Bone and Joint Surgery. American Volume, 53, 275-286.

[62]   Slack, C., Flint, M.H. and Thompson, B.M. (1984) The effect of tension load on isolated embryonic chick tendons in organ culture. Connective Tissue Research, 12, 229-247.

[63]   Woo, S.L.Y., Ritter, M.A., Amiel, D., Sanders, T.M., Gomez, M.A., Kuei, S.C., Garfin, S. R. and Akeson, W.H. (1980) The biomechanical and biochemical properties of swine tendons: Long term effects of exercise on the digital extensors. Connective Tissue Research, 7, 177-183.

[64]   Woo, S.L.Y., Wang, C.W., Newton, P.O. and Lyon, R.M. (1990) The response of ligaments to stress deprivation and stress enhancement: Biomechanical studies. In: Daniel, D.M., Akeson, W.H. and O’Connor, J.J., Eds., Knee ligaments: Structure, Function, Injury, and Repair, Raven Press, New York, 122-129.

[65]   Dejam, A., Hunter, C.J., Tremonti, C., Pluta, R.M., Hon, Y.Y., Grimes, G., Partovi, K., Pelletier, M.M., Oldfield, E.H., O Cannon, R., Schechter, A.N. and Gladwin, M.T. (2007) Nitrate infusion in humans and nonhuman primates: Endocrine effects, pharmacokinetics, and tolerance formation. Circulation, 116, 1821-1831.

[66]   Zhou, M.S., Schulman, I.H. and Raij, L. (2004) Nitric oxide, angiotensin 11, and hypertension. Seminars in Nephrology, 24, 366-378.

[67]   Fujii, Y., Guo, Y. and Hussain, S.N. (1985) Regulation of nitric oxide production in response to skeletal muscle activation. Journal of Applied Physiology, 85, 2330-2336.

[68]   Pye, D., Palomero, J., Kabayo, T. and Jackson, M.J. (2007) Real-time measurement of nitric oxide in single mature mouse skeletal muscle fibres during contractions. The Journal of Physiology, 581, 309-318.

[69]   Ferreira, A.A., Kwasniewski, .F.H., Delani, T.C. Torres, M.G., Silva, M.A., Caparroz-Assef, S.M., Cuman, R.K. and Bersani-Amado, C.A. (2007) Acute immune and non-imune inflammatory response in spontaneously hypertensive rats and normotensive rats. Role of endogenous nitric oxide. Inflammation, 30, 198-204.

[70]   Lizarbe, T.R., Garcia-Roma, C., Tarin, C., Saura, M., Calvo, E., López, J.A, López-Otín, C., Folgueras, A.R., Lamas, S. and Zaragoza, C. (2008) Nitric oxide elicits functional MMP-13 protein tyrosine nitration during wound repair. The FASEB Journal, 22, 3207-3215.

[71]   Fukumura, D., Gohongi, T., Kadambi, A., Izumi, Y., Ang, J., Yun, C.O., Buerk, D.G., Huang, P.L. and Jain, R.K. (2001) Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability. Proceedings of the National Academy of Sciences of the United States of America, 98, 2604-2609.

[72]   Williams, R.S. and Annex, B.H. (2004) Plasticity of myocytes and capillaries: A possible coordinating role for VEGF. Circulation Research, 95, 7-8.

[73]   Hudlicka, O. (1998) Is physiological angiogenesis in skeletal muscle regulated by changes in microcirculation? Microcirculation, 5, 7-23.

[74]   Buckwalter, J.A., Einhorn, T.A., Bolander, M.E., Crusess, R.L. (1996) Healing of the musculoskeletal tissues. In: Rockwood Jr., C.A., Green, D.P., Bucholtz, R.W. and Heckman, J.D., Eds., Fractures in Adults, 4th Edition, Lippincott-Raven, Philidolphia, 261-304.

[75]   Mathew, S., Arandjelovic, S., Beyer, W.F., Gonias, S.L. and Pizzo, S.V. (2003) Characterization of the interaction between alpha2-macroglobulin and fibroblast growth factor-2: The role of hydrophobic interactions. Biochemical Journal, 374, 123-129.

[76]   Proctor, R.A., Textor, J.A., Vann, J.M. and Mosher, D.F. (1985) Role of fibronectin in human monocyte and macrophage bactericidal activity. Infection and Immunity, 47, 629-637.

[77]   Mosesson, M.W. (1984) The role of fibronectin in monocyte/macrophage function. Progress in Clinical and Biological Research, 154, 155-175.

[78]   Melzack, R. (2005) Evolution of the neuromatrix theory of pain. The Prithvi Raj lecture: Presented at the third world congress of world institute of pain, Barcelona 2004. Pain Practice, 5, 85-94.

[79]   Altier, N. and Stewar, J. (1999) The tachykinin NK-1 receptor antagonist, RP-67580, infused into the ventral tegmental area prevents stress-induced analgesia in the formalin test. Physiology & Behavior, 66, 717-721.

[80]   Altier, N. and Stewart, J. (1999) The role of dopamine in the nucleus accumbens in analgesia. Life Sciences, 65, 2269-2287.

[81]   Morgan, M.J. and Franklin, K.B. (1990) 6-Hydroxydopamine lesions of the ventral tegmentum abolish D-amphetamine and morphine analgesia in the formalin test but not in the tail flick test. Brain Research, 519, 144-149.

[82]   Taylor, B.K., Joshi, C. and Uppal, H. (2003) Stimulation of dopamine D2 receptors in the nucleus accumbens inhibits inflammatory pain. Brain Research, 987, 135-143.

[83]   Blum, K., Han, D., Giordano, J., Lohmann, R., Braverman, E.R., Madigan, M.A., Barh, D., Femino, J., Hauser, M., Downs, B.W. and Simpatico, T. (2013) Neurogenetics and nutrigenomics of reward deficiency syndrome (RDS): Stratification of addiction risk and mesolimbic nutrigenomic manipulation of hypodopaminergic function. Chapter-18, In: Barh, D., Dhawan, D. and Ganguly, N.K., Eds., Omics for Personalized Medicine, 1st Edition, Springer, Berlin.

[84]   Magnusson, J.E. and Fisher, K. (2000) The involvement of dopamine in nociception: The role of D1 and D2 receptors in the dorsolateral striatum. Brain Research, 855, 260-266.

[85]   Hagelberg, N., Martikainen, I.K., Mansikka, H., Hinkka, S., Nagren, K., Hietala, J., Scheinin, H. and Pertovaara, A. (2002) Dopamine D2 receptor binding in the human brain is associated with the response to painful stimulation and pain modulatory capacity. Pain, 99, 273-279.

[86]   Hagelberg, N., Kajander, J.K., Nagren, K., Hinkka, S., Hietala, J. and Scheinin, H. (2002) Mu-receptor agonism with alfentanil increases striatal dopamine D2 receptor binding in man. Synapse, 45, 25-30.

[87]   Hagelberg, N., Forssell, H., Rinne, J.O., Scheinin, H., Taiminen, T., Aalto, S., Luutonen, S., Nagren, K. and Jaaskelainen, S. (2003) Striatal dopamine D1 and D2 receptors in burning mouth syndrome. Pain, 101, 149-154.

[88]   Chen, T.J., Blum, K., Waite, R.L., Meshkin, B., Schoolfield, J., Downs. B.W., Braverman, E.E., Arcuri, V., Varshavskiy, M., Blum, S.H., Mengucci, J., Reuben, C. and Palomo, T. (2007) Gene\narcotic attenuation program attenuates substance use disorder, a clinical subtype of reward deficiency syndrome. Advances in Therapy, 24, 402-414.

[89]   Blum, K., Braverman, E.R., Holder, J.M., Lubar, J.F., Monastra, V.J., Miller, D., Lubar, J.O., Chen, T.J. and Comings, D.E. (2000) Reward deficiency syndrome: A biogenetic model for the diagnosis and treatment of impulsive, addictive, and compulsive behaviors. Journal of Psychoactive Drugs, 32, 1-112.

[90]   Elovainio, M., Jokela, M., Kivimaki, M., Pulkki-Raback, L., Lehtimaki, T., Airla, N. and Keltikangas-Jarvinen, L. (2007) Genetic variants in the DRD2 gene moderate the relationship between stressful life events and depressive symptoms in adults: Cardiovascular risk in young Finns study. Psychosomatic Medicine, 69, 391-395.

[91]   Lawford, B.R., Young, R., Noble, E.P., Kann, B., Ritchie, T. (2006) The D2 dopamine receptor (DRD2) gene is associated with co-morbid depression, anxiety and social dysfunction in untreated veterans with post-traumatic stress disorder. European Psychiatry, 21, 180-185.

[92]   Dziedzicka-Wasylewska, M. (1996) The effect of imipramine on the amount of mRNA coding for rat dop posttraumatic stress disorder: A study and replication. Biological Psychiatry, 40, 368-372.

[93]   Kreek, M.J. and Koob, G.F. (1998) Drug dependence: Stress and dysregulation of brain reward pathways. Drug and Alcohol Dependence, 51, 23-47.

[94]   Comings, D.E., Muhleman, D. and Gysin, R. (1990) Dopamine D2 receptor (DRD2) gene and susceptibility to Prefrontal cortical dopamine depletion enhances the responsiveness of mesolimbic dopamine neurons to stress. Brain Research, 521, 311-315.

[95]   Deutch, A.Y. and Clark, W.A., Roth, R.H. (1997) Amine D2 autoreceptors. European Journal of Pharmacology, 337, 291-296.

[96]   Kalivas, P.W., Abhold, R. (1987) Enkephalin release into the ventral tegmental area in response to stress: Modulation of mesocorticolimbic dopamine. Brain Research, 414, 339-348.

[97]   Blum, K., Trachtenberg, M.C., Elliott, C.E., Dingler, M.L., Sexton, R.L., Samuels, A.I. and Cataldie, L. (1988) Enkephalinase inhibition and precursor amino acid loading improves inpatient treatment of alcohol and polydrug abusers: Double-blind placebo-controlled study of the nutritional adjunct SAAVE. Alcohol, 5, 481-493.

[98]   Hashimoto, T., Hussien, R., Cho, H.S. and Kaufer, D. (2008) Brooks GA: Evidence for the mitochondrial lactate oxidation complex in rat neurons: Demonstration of an essential component of brain lactate shuttles. PLoS One, 3, e2915.

[99]   Hashimoto, T. and Brooks, G.A. (2008) Mitochondrial lactate oxidation complex and an adaptive role for lactate production. Medicine & Science in Sports & Exercise, 40, 486-494.

[100]   Nisoli, E., Cozzi, V. and Carruba, M.O. (2008) Amino acids and mitochondrial biogenesis. American Journal of Cardiology, 101, S22-S25.

[101]   Bongrazio, M., Da Silva-Azevedo, L., Bergmann, E.C., Baum, O., Hinz, B., Pries, A.R. and Zakrzewicz, A. (2006) Shear stress modulates the expression of thrombospondin-1 and CD36 in endothelial cells in vitro and during shear stress-induced angiogenesis in vivo. International Journal of Immunopathology & Pharmacology, 19, 35-48.

[102]   Chinsomboon, J., Ruas, J., Gupta, R.K., Thom, R., Shoag, J., Rowe, G.C., Sawada, N., Raghuram, S. and Arany, Z. (2010) The transcriptional coactivator PGC-1α mediates exercise-induced angiogenesis in skeletal muscle. Proceedings of the National Academy of Sciences of the United States of America, 106, 21401-21406.

[103]   Akhmetov, I.I., Astranenkova, I.V. and Rogozkin, V.A. (2007) Association of PPARD gene polymorphism with human physical performance. Molekuliarnaia Biologiia, 41, 852-857.

[104]   Lo, I.K., Ou, Y., Rattner, J.P., Hart, D.A., Marchuk, L.L., Frank, C.B. and Rattner, J.B. (2002) The cellular networks of normal ovine medial collateral and anterior cruciate ligaments are not accurately recapitulated in scar tissue. Journal of Anatomy, 200, 283-296.

[105]   Georgiev, G.P., Vidinov, N.K. and Kinov, P.S. (2010) Histological and ultrastructural evaluation of the early healing of the lateral collateral ligament epiligament tissue in a rat knee model. BMC Musculoskeletal Disorders, 11, 117.

[106]   Ohio Department of Health (2012) Ohio drug poisoning fact sheet: Epidemic of prescription drug overdoses in Ohio.

[107]   Lanier, W.A. (2010) Prescription opioid overdose deaths —Utah, 2008-2009. The 59th Annual Epidemic Intelligence Service Conference, Atlanta, 19-23 April 2010, 10-13.

[108]   Franklin, G.M., Rahman, E.A., Turner, J.A., Daniell, W.E. and Fulton-Kehoe, D. (2009) Opioid use for chronic low back pain: A prospective, population-based study among injured workers in Washington State, 2002-2005. Clinical Journal of Pain, 25, 743-751.

[109]   Yoast, R., Williams, M.A., Deitchman, S.D. and Champion, H.C. (2001) Report of the council on scientific affairs: Methadone maintenance and needle-exchange programs to reduce the medical and public health conesquences of drug abuse. Journal of Addictive Disease, 20, 15-40.