HBO Addiction special on the web This is the web format of a special addiction program by HBO. The material covers issues such as who pays for addiction treatment, and drug treatment for adolescents.
Special Problems of Adolescents with Opioid Use Disorders < List of psychosocial issues
http://www.needymeds.org/ The Needymeds website provides information on the Suboxone assistance program, a program that offers free suboxone medication to low-income patients who meet all eligibility requirements. It also includes important contact information, suboxone doses that are part of the program, the roles of the physician and patient in the application process, and application requirements.
Vivitrol for opioid dependence << Web LINK
asam-national-practice-guideline-supplement – for opioid addiction – ASAM practice guideline
Clinical drug testing in the office pDF < Full service information
DSM-5-Opioid-Use-Disorder-Diagnostic-Criteria Checklist Criteria Form
Language of addiction medicine A guide for using non-stigmatizing language when working with patients who have substance use disorders.
Practitioners manual of controlled substances act Web site for controlled substances act Manual written by the DEA to assist physicians in understanding and complying with the Federal Controlled Substances Act. Topics covered include recordkeeping requirements, rules regarding prescription, and security requirements.
VERMONT BUPRENORPHINE practice guideline < good resource
Alexander ‘Sasha’ Shulgin is the scientist behind more than 200 psychedelic compounds including MDMA, more commonly known as Esctasy. Considered to be one of the the greatest chemists of the twentieth century, Sasha’s vast array of discoveries have had a profound impact in the field of psychedelic research. ‘Dirty Pictures’ delves into the lifework of Dr. Shulgin and scientists alike, explores the world of these scientists; their findings and motivations, their ideas, and their beliefs as to how research in this particular field can aid in unlocking the complexities of the mind.
Buprenorphine is morphine-like but is 25 to 50 times more potent [15,16] Maintenance drugs to treat opioid dependence BMJ / Heroin anticraving medications A systematic review. It is noteworthy that buprenorphine has very low oral bioavailability because it undergoes extensive first pass metabolism. However, its bioavailability is substantial enough that sublingual (SL) administration makes this a feasible treatment for opioid dependence. The mean time to peak plasma concentration following SL administration varies and can range from 40 minutes to 3.5 hours. Buprenorphine is highly protein bound (96%) and has a large volume of distribution. It is metabolized extensively to norbuprenorphine by N-dealkylation, primarily through cytochrome P450 (CYP) 3A4. The half-life of buprenorphine is long, and there is considerable variation in reported values of terminal elimination, with mean values ranging from 3 to 44 hours. Most of a dose of buprenorphine is eliminated in the feces, with approximately 10–30% excreted in urine. Buprenorphine has an extremely high affinity and slow dissociation from opioid receptors, providing simultaneous opioid blockade and agonist effects. The duration of action of buprenorphine is longer than these pharmacokinetic parameters, resulting in suppression of opioid withdrawal symptoms for 2 to 3 days after cessation of use. Naloxone is added to buprenorphine for the treatment of opiate dependence and to prevent intravenous diversion . However, the efficacy of buprenorphine is not affected by the combination because the half-life for buprenorphine is much longer than for naloxone (up to 32 vs. 1 hour for naloxone) and naloxone is poorly absorbed sublingually relative to buprenorphine. Plasma levels of naloxone are lower and decline much more rapidly than those for buprenorphine The New Kid on the Block—Incorporating Buprenorphine into a medical toxicology practice 2015. The pharmacokinetics of buprenorphine does not appear to be influenced by the presence of naloxone. However, the presence of naloxone does appear to reduce the degree of appeal and reward, supporting the recommendation for combination products over mono products for longer term prescribing for high risk individuals Can the chronic administration of the combination of buprenorphine and naloxone block dopaminergic activity causing anti-reward and relapse potential b.
Toxicity from methadone and the risks of a drug overdose and death is much higher than for buprenorphine. Phase 1 metabolism of nearly 80% of pharmaceutical drugs in use today is the province of enzymes that are synthesized by the cytochrome P450 (CYP) family. Gene duplications and gene polymorphisms CYP2D6, CYP2C19 and CYP2C9 are most frequently responsible for variations in drug metabolism. Approximately 5% of Europeans, 1% of Asians, 5–14% of Caucasians and 5% of Africans lack CYP2D6 activity. These individuals are known as poor metabolizers Can the chronic administration of the combination of buprenorphine and naloxone block dopaminergic activity causing anti-reward and relapse potential b///Genetics of pain, opioids, and opioid responsiveness//Effect of genetic factors on opioid action . Although methadone and buprenorphine are metabolized by the 3A4 system, methadone metabolism also involves 2D6 and 2B6, resulting in a significant risk for clinically significant drug interactions with methadone compared to buprenorphine. Enzyme inhibitors and inducers of the 3A4 system can change levels of methadone and buprenorphine, however, the partial agonist effects of buprenorphine appear to protect against overdose mortality. 3A4 inducers such as carbamazepine and barbiturates result in clinically significant lowering of methadone drug levels, resulting in the emergence of withdrawal symptoms and raising of methadone doses for symptom stabilization. Notably, Seifert Mood and affect during detoxification of opiate addicts – comparing bup and methadone found better clinical outcomes and more effective short-term relief of affective disturbances resulted from combining buprenorphine and carbamazepine than from combining carbamazepine with methadone when detoxifying multi-drug opiate addicts. An explanation of this interesting effect may be that while buprenorphine has similar effects on enzyme induction as methadone the reported difference could be due to buprenorphine’s high affinity and slow dissociation receptor binding characteristics.
Theoretically, the use of naloxone or naltrexone alone at therapeutic doses also blocks the release of DA in the reward site of the brain . While, clinically many patients on naltrexone alone may still experience pleasure and may not always experience anhedonia, this suggests a highly complex mechanism
In the long term, administration of buprenorphine will result in an attenuation of mu receptor occupancy of the natural opioid enkephalin and will eventually, like naloxone, result in reduced release of DA at the accumbens brain region . This, in turn, may lead to generalized drug seeking behavior
Dopamine (DA) antagonists have been found to markedly potentiate many of the central effects of morphine and other opioids, in contrast, direct and indirect DA agonists have reversed the central effects of opioids. Even more importantly in low to moderate doses, DA antagonists that selectively and appreciably inhibit DA release can also mimic many of these effects Can the chronic administration of the combination of buprenorphine and naloxone block dopaminergic activity causing anti-reward and relapse potential b. In fact, in the neostriatum the biosynthesis of opioid peptides is most dependent on the dopaminergic transmission while, variations in the amplitude of the of mu opioid receptor density and preprodynorphin and preproenkephalin messenger RNA levels, indicate that the regulation, of pallidal and neostriatal mu opioid receptors is more susceptible to a direct opioid antagonism. Haloperidol was found to cause down-regulation of mu opioid receptors that resulted in adaptive changes that increase enkephalin release and biosynthesis .
Increased enkephalin with an accompanied reduction of availability of mu-receptors prevents enkephalin attenuation of the GABA-mediated effects on pallidal neuronal activity of dopaminergic denervation and leads to a hypodopaminergic function in the long-term . Simply, reduced mu receptors and as such a reduced enkephalin stimulation of mu receptor inhibition onto GABA receptors at the substania nigra, will lead to a reduced neuronal release of dopamine at the nucleus accumbens. It seems parsimonious then, to consider the potential of combining buprenorphine with a natural D2 agonist which bypasses the GABA inhibition step. A recent study has eloquently shown that if the gene that codes for the β3 subunit of the GABA(A) receptor is removed, DA release, enhanced reward learning and even decision – making, is increased, in electrically stimulated neurons, in the nucleus accumbens of β3-knock out (KO) mice.
The clinical relevance, in terms of long term therapy with buprenorphine/naloxone combination, involves the development of a hypodopaminergic state even independent of genetic predisposition, like carrying DRD2 A1 allele with resultant 30–40% reduction in D2 receptor density. This leads to unwanted mood swings and enhanced drug craving and seeking. Moreover, based on an analysis that covered the whole gene locus from the DRD2 promoter to the ANKK1 rs1800497C>T polymorphism DRD2 genetic polymorphisms help to identify those at risk for opiate addiction and to modulate the dosage requirements necessary for methadone or buprenorphine substitution therapy.Genetic variants altering dopamine D2 receptor expression or function modulate the risk of opiate addiction and the dosage requirements of methadone substitution
KB220Z is a formulation that consists of enkephalinase-catecholamine– methyl-transferase (COMT)/monoamine –oxidase (MOA) inhibition therapy and amino-acid neurotransmitter precursors that work, in synchrony, to support brain reward function . This is the first neuroadaptive formulation known to activate the brain reward circuitry and is called Neuroadaptagen Amino Acid Therapy™ (NAAT) [44 – This document presents evidence supporting the role of the KB220/KB220Z neuroadaptagens consisting of amino-acid neurotransmitter precursors and enkephalinase-catecholamine-methyl-transferase (COMT) inhibition therapy called Neuroadaptagen Amino Acid Therapy (NAAT) in brain reward function. It is becoming increasingly clear that this novel formulation is the first neuroadaptagen known to activate the brain reward circuitry. Ongoing research repeatedly confirms the numerous clinical effects that ultimately result in significant benefits for victims having genetic antecedents for all addictive, compulsive and impulsive behaviors. These behaviors are correctly classified under the rubric of”Reward Deficiency Syndrome” (RDS). We are proposing a novel addiction candidate gene map. We present preliminary findings in the United States using qEGG and in China using Functional Magnetic Resonance Imaging (fMRI) regarding the effects of oral NAAT on the activation of brain reward circuitry in victims of SUD. In unpublished data utilizing an fMRI 2X2 design at resting state, NAAT in comparison to placebo shows activation of the caudate brain region and potentially a smoothing out of heroin-induced putamen (a site for emotionality) abnormal connectivity. Although awaiting final analysis, if confirmed by ongoing studies in China coupled with published qEEG results in America, showing an increase in alpha and low beta, NAAT may be shown to impact treatment outcomes Chen TJ, Blum K, Chen AL, Bowirrat A, Downs WB, et al. Neurogenetics and clinical evidence for the putative activation of the brain reward circuitry by amino-acid precursor-catabolic enzyme inhibition therapeutic agent (a Neuroadaptagen): Proposing an addiction candidate gene panel map. J Psychoactive Drugs. 2011; 43:108–127.]. Numerous clinical effects that benefit victims of “Reward Deficiency Syndrome” (RDS) are repeatedly confirmed in ongoing research. RDS is a term that describes hypodopaminergic function in the mesolimbic system of the brain. Hypodopaminergic function, can be the trigger for compensatory addictive, compulsive and impulsive behaviors that can elicit extreme DA release that in turn results in DRD2 down -regulation [45 — The dopaminergic system, and in particular the dopamine D2 receptor, has been implicated in reward mechanisms. The net effect of neurotransmitter interaction at the mesolimbic brain region induces “reward” when dopamine (DA) is released from the neuron at the nucleus accumbens and interacts with a dopamine D2 receptor. “The reward cascade” involves the release of serotonin, which in turn at the hypothalmus stimulates enkephalin, which in turn inhibits GABA at the substania nigra, which in turn fine tunes the amount of DA released at the nucleus accumbens or “reward site.” It is well known that under normal conditions in the reward site DA works to maintain our normal drives. In fact, DA has become to be known as the “pleasure molecule” and/or the “antistress molecule.” When DA is released into the synapse, it stimulates a number a DA receptors (D1-D5) which results in increased feelings of well-being and stress reduction. A consensus of the literature suggests that when there is a dysfunction in the brain reward cascade, which could be caused by certain genetic variants (polygenic), especially in the DA system causing a hypodopaminergic trait, the brain of that person requires a DA fix to feel good. This trait leads to multiple drug-seeking behavior. This is so because alcohol, cocaine, heroin, marijuana, nicotine, and glucose all cause activation and neuronal release of brain DA, which could heal the abnormal cravings. Certainly after ten years of study we could say with confidence that carriers of the DAD2 receptor A1 allele have compromised D2 receptors. Therefore lack of D2 receptors causes individuals to have a high risk for multiple addictive, impulsive and compulsive behavioral propensities, such as severe alcoholism, cocaine, heroin, marijuana and nicotine use, glucose bingeing, pathological gambling, sex addiction, ADHD, Tourette’s Syndrome, autism, chronic violence, posttraumatic stress disorder, schizoid/avoidant cluster, conduct disorder and antisocial behavior. In order to explain the breakdown of the reward cascade due to both multiple genes and environmental stimuli (pleiotropism) and resultant aberrant behaviors, Blum united this hypodopaminergic trait under the rubric of a reward deficiency syndrome. Blum K, Braverman ER, Holder JM, Lubar JF, Monastra VJ, et al. Reward deficiency syndrome: a biogenetic model for the diagnosis and treatment of impulsive, addictive, and compulsive behaviors. J Psychoactive Drugs. 2000; 32(Suppl):i–iv. 1–112]. Gentle activation of brain reward circuitry using NAAT (KB200Z) that has the potential to up –regulate DAD2 receptor density has been demonstrated using qEGG in the United States Overcoming qEEG Abnormalities and Reward Gene Deficits during Protracted Abstinence in Male Psychostimulant and Polydrug Abusers Utilizing Putative Dopamine D2 Agonist Therapy —- Resources :Reward-Deficiency-Syndrome-Studies-of-KB220-Variants-and-Molecular-Neurobiology < Research links
A polymorphism 4 R/4R (homozygous) which relates to a high MOA-A activity which could lead to a more rapid degradation of Dopamine (DA) in the mitochondria once the released DA is sequestered back into the pre-synaptic neuron. Genotyping may also reveal polymorphisms in the dopamine transporter gene (DAT1) whereby if one carried homozygote 9R/9R, it suggests that the transporter system is highly active and as such sequesters higher amounts of DA (higher uptake) to re-enter the presynaptic neuron as well. If one also also carries the heterozygous A/G (Val) polymorphism which will result in a higher activity of COMT and as such the DA in the synapse will be broken down at a faster rate. Taken together these results strongly suggest a “hypodopaminergic state”. Along with this proposed “hypodopaminergic state” (or genetic trait) if a subject also is heterogeneous for polymorphism in the GABA receptor beta subunit (183) this could result in reduced GABA sensitivity leading to anxiousness or stress. Genotyping of the DA receptors (D2,3,4) were found to be normal in terms of receptor densities as well as the Mu opiate receptor. If one possesses the homozygote serotonin transporter L/L – this may be protective against alcohol seeking behavior. Understanding this important genotyping information provides impetus to development of a protocol that converts her low dopaminergic state to a higher dopaminergic state. An increase in synaptic DA can be facilitated by the ingredients in KB220Z. Rhodiola rosea is known to block MOA and COMT activity and both phenylalanine and tyrosine impede the high activity of the molecules involved in DAT gate (leading a reduced DAT activity). Further it is conjectured that enhanced quanta of DA could offset the anxiety due to GABA polymorphisms that result in reduced DA and as such increased norepinephrine activity (stress molecule).
Clinical utilization of a natural dopaminergic activator to wean patients from long-term buprenorphine/naloxone combination therapy in chemical dependency treatment facilities and programs may be found in the use of KB200Z.
D-phenylalanine (D-Pha) a component of KB200Z acts as an analgesic due to its known enkephalinase inhibition properties Hypothesizing that brain reward circuitry genes are genetic antecedents of pain sensitivity and critical diagnostic and pharmacogenomic treatment targets for chronic pain conditions.//Can Genetic Testing Coupled with Enhanced Dopaminergic Activation Reduce Recidivism Rates in the Workers Compensation Legacy Cases/////Can Genetic Testing Coupled with Enhanced Dopaminergic Activation Reduce Recidivism Rates in the Workers Compensation Legacy Cases/////Can Genetic Testing Provide Information to Develop Customized Nutrigenomic Solutions for Reward Deficiency Syndrome.
There is clear evidence that KB220Z significantly influences drug-induced withdrawal symptoms , building up to relapse , leaving against medical advice (AMA rates)  drug hunger , regulation of dysregulated widespread delta waves in psychostimulant abusers  as well as alcohol and opiate addicts  and an enhanced happiness .
http://addictionsupplements.com/synapta/index.html < Nutraceutical link for KB220 and research articles
Moreover, neuroimaging studies of buprenorphine/naloxone combinations do not support an effect on cingulate-gyrus activation. The cingulate-gyrus is thought to be the loci of relapse prevention Acute effects of sublingual buprenorphine on brain responses to heroin-related c ues in early-abstinentShow more ….
If an intervention that consisted of neuro-therapy to reduce pain and the use of neuroadpatgen-amino-acid – therapy (NAAT), to enhance “dopamine sensitivity”, could attenuate pain at (10–60%) the savings may be counted in billions. Such a program could consist, for example, of KB220Z; cranial stimulation, electrotherapy for pain control and biofeedback.
It is noteworthy that one contributor to buprenorphine withdrawal syndrome are the high dosages used for Suboxone®/Subutex ORT. Given that buprenorphine is about 40 times more potent than morphine, each 2 mg capsule or film is the equivalent of 80 mg Morphine sulfate. In fact sublingual (SL) buprenorphine is often referred to as “high dose buprenorphine”. So even if you stop buprenorphine at 1/2 the smallest dosage form, that is still like stopping Kadian (oral morphine) 20 mg two-times a day (BID) abruptly without a wean, though with buprenorphine’ long half-life it may be less intense but last longer similar to methadone withdrawal. We must underscore the clinical fact that even patients coming off of ¼ mg of Suboxone® have severe withdrawal. It is not the rate of taper but the rate of reactivation of reward deficit. Recently, the 7 day Butrans® patch became available, and is FDA approved for pain. The highest dosage it comes in is 20 mcg/hour; this is less than 1/2 mg per day. One strategy that could be used is to wean SL buprenorphine to 1 mg/day, then change over to the Butrans patch weaning from 20 to 15 to 10 mcg/h, though it would take some time and insurance does not typically cover it. So there may not be anything special about Buprenorphine withdrawal as compared to other opioids other than the incredibly high dosages of Suboxone®. The smallest pill/film available contains 2 mg SL buprenorphine, although it is the smallest dosage, it is actually a very high opioid dosage.
While the pain continues it is bearable with KB220Z due to its ability to activate dopaminergic pathways. Dopamine tone is involved in the inhibition of inflammation and chronic pain . Tonic pain inhibition is regulated by activated mesolimbic dopamine neurons that project into the nucleus accumbens from the cell bodies of the ventral tegmental area. When this pain-suppression system is activated by acute stress endogenous opioids and substance P are released. However, a reduction of nucleus accumbens dopamine output and development of persistent hyperalgesia are produces by prolonged exposure to unavoidable stress.
Unlike buprenorphine/naloxone combination  which does not activate the cingulate gyrus (a site for drugs abuse relapse) KB220Z activates the cingulate gyrus and induces regulation of aberrant electrical dysregulation (widespread theta) in the cingulated gyrus as measured by qEEG analysis [48,59]. These results support our earlier reports , that KB220Z/KK220IV are natural dopaminergic agonists and have potential as therapeutic agents for weaning, relapse prevention Expanding treatment capacity for opioid dependence with office-based treatment with buprenorphine National surveys of physicians. and to provide benefit in opioid dependence – Suboxone® treatment programs as an adjunct to therapy in the short term . It is noteworthy, that most patients don’t relapse after a few years because of cue reactivity originating in PFC-cingulate gyrus and possibly disruption of executive functioningNeuropsychopharmacology and neurogenetic aspects of executive functioning /////Executive Dysfunction instead it is usually due to stress, re-exposure to narcotics, lowering of the dose of non-drug recovery equivalents and complacency.
Recently, Diana The Dopamine Hypothesis of Drug Addiction and Its Potential Therapeutic Value pointed out that imaging studies visualized reduced dopamine receptor density accompanied by decreased release of endogenous dopamine in the ventral striatum of alcohol, cocaine and heroin dependent subjects, proof of dopamine deficiency in drug dependant subjects. This new objective study supports the concept of reward deficiency syndrome  and its treatment with dopamine agonist therapy to reduce cravings and prevent relapse and drug seeking behaviorIt is noteworthy, that when Doehring et al.  analyzed the whole DRD2 gene locus they found that DRD2 genetic polymorphisms regulate both opiate addiction risk and ORT dosage requirements. Relevant to this article Seifert et al.  found that compared to carbamazepine and methadone, patients on the buprenorphine and carbamazepine combination demonstrated significantly better psychological state with reduced, sensitiveness, tiredness and depression by week two of detoxification.
The daily use of KB220Z, a natural dopamine agonist neuroadaptagen showing dopaminergic activation properties as measured by qEEG and fMRI, provides an alternative substitution adjunctive modality influencing brain reward circuitry [44,46,59,75–83].
Clinically Combating Reward Deficiency Syndrome (RDS) with Dopamine Agonist Therapy as a Paradigm Shift Dopamine for Dinner Coupling Neurogenetics (GARS™) and a Nutrigenomic Based Dopaminergic Agonist to Treat Reward Deficiency Syndrome (RDS) Targeting Polymorphic Reward Genes for Carbohydrate Addiction Al