Abstract— The proposal will introduce the use of Transcranial Magnetic Stimulation (TMS) in conjunction with Methadone Maintenance Treatment (MMT) to treat individuals with opiate dependence.

Drug addiction/ dependence places a great deal of medical, financial and emotional stress on society. The negative effects of drug addiction are seen in overdose and health complications, family disintegration, loss of employment and criminal activity [1]. The National Institute on Drug Abuse (NIDA), estimates that the total cost of drug abuse in the United States exceeds US$600 billion annually. These findings provide significance for further research into the neuronal effects of addictive drugs, and novel treatment strategies to dilute these effects.

Opiate addiction is a re-curing three step abuse cycle: anticipation/preoccupation, binge, intoxication and withdrawal/negative affect [2]. The withdrawal/negative affect phase of the abuse cycle is characterized by anxiety-like decreases in reward as measured by increases in threshold for brain stimulation reward [2]. The danger  is increased sensitivity of opioid receptor transduction mechanisms in the nucleus accumbens during opiate withdrawal. MMT works by helping the patient reduce their dependence on opiates slowly [3]. Other opioids can be used for this purpose, but methadone has the advantage of a long half-life resulting in only daily dosing with a smaller peak to trough plasma concentration ratio where the peaks represent potential overdose and the troughs represent withdrawal [4].

TMS is a neuro-stimulation technique which utilizes the principle of electromagnetic induction of electric fields in the brain. This field can depolarize neurons and modulate cortical excitability. [3]

  1. PROBLEM STATEMENT

Methadone’s major target is the μ-opioid receptor (MOP). This primary binding site is responsible for both the efficacy of treatment and the major adverse effects [4]. Overdose on MMT is a possibility, and can be fatal due to respiratory depression. Overstimulation of the MOP in conjunction with other opioid receptors can lead to death.

III.       PROPOSED SOLUTION

A wearable cap which can apply TMS and monitor EEG. This approach will significantly reduce the risk of overdose for MMT patients by recording continuous EEG and modulating the neurons and receptors responsible. EEG recordings will be used to determine dangerous levels of stimulation within the brain in order to modulate the TMS. Data recordings will also be transmitted to health care professionals via WiFi or LTE network to enable remote monitoring of MMT patients. This allows for optimal dosing and further reduces the risk of overdose.

  1. TIMELINE

Proposal approval (sept.30th), further research (Oct. 15th), design (Oct. 30th), presentation (Nov. 8th)

INTRODUCTION/BACKGROUND

Drug addiction/ dependence places a great deal of medical, financial and emotional stress on society. The negative effects of drug addiction are seen in overdose and health complications, family disintegration, loss of employment and criminal activity [1]. The National Institute on Drug Abuse (NIDA), estimates that the total cost of drug abuse in the United States exceeds US$600 billion annually, with opioids contributing $1.2 billion. It is especially alarming to note a sharp increase in abuse among teenagers. These findings provide significance for further research into the neuronal effects of addictive drugs, and novel treatment strategies to dilute these effects. This paper will discuss the use of Transcranial Magnetic Stimulation (TMS) in conjunction with Methadone Maintenance Treatment (MMT) to treat individuals with opiate dependence. Specifically, we introduce a wearable cap which applies TMS to individuals and monitors their MMT via continuous EEG recording. Advantages, limitations and future directions of this approach will be discussed.

Opioids

Opioids are a broad category of drugs characterized by their morphine-like effects, including opiates, semi-synthetic drugs derived from opiates (such as heroin, hydrocodone, hydromorphone, oxycodone and oxymorphone), and synthetic drugs which are not directly derived from opiates (such as fentanyl and methadone). All opioids are drugs of high abuse potential and thus abusers of opioids are the target for our treatment.

Opioid addiction is a re-curing three step abuse cycle: anticipation/preoccupation, binge, intoxication and withdrawal/negative affect [2]. Prolonged use leading to dependence is accompanied by many neuronal changes in the brain which result in the symptoms of withdrawal. Multiple sources of reinforcement are present in this cycle. These include the positive reinforcement of the binge intoxication stage, the negative reinforcement of drug taking to avoid a negative emotional state in the withdrawal stage and the conditioned reinforcement in the anticipation stage.

Figure 1: Stages of abuse [1].

 

 

Transcranial Magnetic Stimulation

Trans

 

Methadone Maintenance Treatment

Methadone maintenance treatment works by helping the patient reduce their dependence on opiates slowly [3]. Other opioids can be used for this purpose, but methadone has the advantage of a long half-life resulting in only daily dosing with a smaller peak to trough plasma concentration ratio where the peaks represent potential overdose and the troughs represent withdrawal [4].

 

  1. METHODOLOGY

 

  1. Literature review of relevant topics

Opioids and the mechanisms of addiction were studied in order to understand the nature and gravity of the problem. Following, a study of existing solutions was completed, and deficiencies in the solutions was identified. This provided the significance of designing a new treatment strategy to overcome the deficiencies of current solutions. Finally, study of alternative scientific methods for accomplishing the same tasks as existing solutions was done.

  1. Theorization

Following the literature review, ideas were theorized and discussed within the group. After analysis of feasibility, advantages and disadvantages the proposed solution was identified. A preliminary design of the solution was developed.

  • Proposal and Presentation

A proposal document was submitted for evaluation by the professor. After approval, a presentation was prepared to receive further feedback from classmates.

  1. Final Design and Project Report

The final design was completed including functional block diagrams, example GUIs and pictoral representations of the solution.

A key element to addiction is the neuronal changes specifically in brain reward systems which accompany abuse. Examples of these changes at the neurochemical level include decreases in dopaminergic and serotonergic transmissions in the nucleus accumbens during withdrawal. These decreases in reward neurotransmissions have been hypothesized to contribute to the negative emotional state associated with drug abstinence and vulnerability to relapse [1]. Table 1 shows the neurotransmitters involved in the motivational effects of opioid withdrawal.

 

Table 1: Neurotransmitters Involved in the Motivational Effects of Opiate Withdrawal

Neurotransmitter Activity Effect
Dopamine Decreased Dysphoria
Serotonin Decreased Dysphoria
GABA Decreased Anxiety, panic attacks
Opioid peptide Decreased Dysphoria
Dynorphin Increased Dysphoria
CRF Increased Stress
Norepinephrine Increased Stress
Glutamate Increased Hyper excitability

Furthermore, different neurochemical systems involved in stress modulation may also be active during chronic drug presence in order to restore normal function. This suggests not only a change in function of the neurotransmitters listen in Table 1 during the development of dependence, but also a change in the stress systems. Effectively, reward mechanisms are compromised by disruption of neurochemical systems involved in processing natural reward and anti-reward systems are recruited in the process of neuroadaptation to the chronic exposure of the brain reward system to opioids. Therefore, these systems are the primary targets for both treatment strategies available currently and our proposed solution.

 

 

Current Solutions: Methadone Maintenance Treatment

 

Oral absorption of methadone is rapid with peak plasma concentrations occurring at 2-3 h and bioavailability exceeding 80%.

Methadone’s major target is the μ-opioid receptor (MOP). This primary binding site is responsible for both the efficacy of treatment and the major adverse effects [4]. Overstimulation of the MOP in conjunction with other opioid receptors can be fatal. Overdose on MMT can cause respiratory depression and eventually death. In addition to risk of fata overdose, MMT has an inherent disadvantage in that it is an ineffective treatment, and rather a “functional” maintenance method. Functional here refers to providing the individual to resume regular life in terms of employment, social life and mental health. The majority of patients will resume use of opioids if they stop taking methadone [2]. Studies show that 82% of patients had relapsed to intravenous drug use 10 months after treatment. Due to this, the duration of the treatment is prolonged and in some cases lasts the duration of the patient’s life costing them an extensive amount of money. Finally, MMT can also increase the chance of overdose for patients, if they relapse after treatment. During treatment, the sensitivity of the receptors which respond to the drug of abuse will increase as stimulation decreases. If the patient re-administers their regular abuse dose, the receptors may be overstimulated and lead to overdose.

 

These drawbacks provide significance to the development of new strategies for treating opioid dependence.

Proposed Solution

A wearable cap which can apply TMS and monitor EEG. This approach will significantly reduce the risk of overdose for MMT patients by recording continuous EEG and modulating the neurons and receptors responsible. EEG recordings will be used to determine dangerous levels of stimulation within the brain in order to modulate the TMS. Data recordings will also be transmitted to health care professionals via WiFi or LTE network to enable remote monitoring of MMT patients. This allows for optimal dosing and further reduces the risk of overdose.