Effective & Safe Novel Treatment of Opioid Use Disorder: Unilateral Transcranial Photobiomodulation
Opioid use disorder (OUD) is causing profound suffering, death, and destruction to individuals, families, and societies on a global scale. According to the National Institute on Drug Abuse (1), “The combined healthcare, crime-related, and productivity costs of tobacco, alcohol, and illicit drugs exceed $700 billion a year, but dollars only poorly approximate the devastating human cost of substance use disorders.” According to the CDC, opioids were involved in 42,249 deaths in 2016, a 28% increase over 2015 and 5-fold increase since 1999 (2). The mental suffering of drug abused patients and their families, the physical health complications, the loss of productivity, and the increase in criminality are all catastrophically injurious. Current treatments are obviously not stemming the tide of this disaster and there is a pressing need for additional stand-alone or add-on treatments that are safe and efficacious.
The current evidence-based standard for the treatment for OUD is medication management using buprenorphine (typically in combination with naloxone to prevent misuse) or methadone in relatively low doses to reduce opioid cravings and withdrawal symptoms. Buprenorphine and methadone are substantially more effective than placebo in retaining people in treatment and suppressing illicit opioid use (3, 4). However, there is considerable reluctance to use this approach in some quarters, often from an inaccurate concern that one is substituting one kind of addiction for another. Knudsen et al. (5) estimated that <50% of privately funded substance use disorder treatment programs offer medication management and only about a third of patients with opioid dependence at these programs actually receive it. Further, the dropout rate is high, with estimates that up to 40–50% of patients will discontinue medication management prematurely, frequently within the first month (6–8). Hence, there is a need for effective stand-alone treatments that would be acceptable to individuals and programs that eschew medication management and add-on treatments that can enhance the retention rates and abstinence rates of medication management.
Medication management makes sense pharmacologically but it does not address the underlying psychological and neurobiological factors that place individuals at risk. A complementary or alternative strategy emerges from the work of Schiffer on “Dual-Brain Psychology” (9–12). Based on his clinical experience and on the split-brain studies (13, 14), Schiffer has theorized that, in adulthood, maltreatments, and traumas, especially from childhood, become associated as a persistent trait with one brain hemisphere, either left or right, making the mind of that side immature and prone to seeing the world through the eyes of a traumatized child, affecting the person's affects, thoughts, and behaviors, generally in a negative manner. The other hemisphere has a mental perspective that is more mature and healthier. In his clinical practice, Schiffer uses lateral visual field stimulation to bring forth these different personalities. This is easily accomplished by restricting his patients' vision with taped goggles, their hands, or a letter size envelope to either the left hemifield of the left eye or the right hemifield of the right eye, which is accompanied by enhanced activation throughout the contralateral hemisphere (15). The method and its consequences are best described in his book, Of Two Minds (9), which using transcripts from patient sessions, demonstrated that looking out of one visual field vs. the other led to remarkable changes in personality, in many of his patients, such that he could have conversations with different personalities in the same person, depending on which visual field they were looking out of. Out of one visual field the patient might see Schiffer as harsh and critical as his father had been. He might tend to be critical of himself and if he had a history of drug abuse, he would likely develop drug craving looking out of that lateral visual field, while out of the opposite lateral visual field the patient would generally see Schiffer as supportive and see himself in a positive light. His drug craving would generally be greatly diminished or eliminated. Looking out the first visual field again would usually return the patient to his negative perceptions, thoughts, and actions. Schiffer could have different lengthy conversations with each side, and he would teach the patient to try to encourage the positive side to become more dominate and to recruit that side as a co-therapist in helping the more troubled side. Other than the fact that the lateral visual fields are neurologically connected to the contralateral hemisphere, he does not have a good explanation for his observations, why simple lateral visual stimulation can within seconds alter most patients' psychological state. This effect of lateral visual field stimulation was first reported by Wittling and Schweiger (16) and Wittling and Roschmann (17).
These observations were rigorously tested and well-supported with experiments at our laboratory at McLean Hospital with fMRI (15), near infrared spectroscopy (18), rapid Transcranial Magnetic (rTMS) electroencephalograms (19), evoked potentials (20), and psychometrics (11, 12, 19). Interestingly, while hemispheric valence theories delineate the right hemisphere as the more emotional and/or the more negative (21), Schiffer et al. (18) found that in about 45% of individuals that the more immature personality was actually associated with the left hemisphere. Schiffer proposed that difference in laterality would substantially affect the efficacy of lateralized treatments for depression with rTMS, and confirmed this in two studies (22, 23).
Schiffer then proposed that selectively stimulating the hemisphere associated with the more mature personality would be beneficial in alleviating symptoms of depression, anxiety or drug craving and explored this possibility using transcranial photobiomodulation (tPBM) (24).
Photobiomodulation, formerly called low-level light/laser therapy, is a burgeoning field, which has about 1,500 PubMed citations, most in recent years (25–27). Over decades, these therapies have been used mostly to treat wound healing, musculoskeletal disorder, and gastrointestinal disorders. In 2009 Schiffer and Hamblin and associates (24) performed the first use of transcranial photobiomodulation (tPBM) for the treatment of anxiety and depression. tPBM has been shown to activate mitochondria through near infrared absorption by cytochrome-C (28, 29), increase blood flow (24), integrate and segregate brain networks (30–32), and inhibit the default mode (33). tPBM (29, 34, 35) is a newer part of the burgeoning field of photobiomodulation. tPBM has been used for cognitive enhancement (36–38), sexual disorders (39), traumatic brain injury (31, 40, 41), depression and anxiety disorders (29, 42, 43) and is being explored for other neurological brain disorders (44–46). Zomorrodi and associates found that in volunteer participants tPBM at 810 nm induced significant EEG changes increasing the power of alpha, beta and gamma and decreasing lower frequencies in a blinded RCT. They also found evidence for improvements in neural connectivity. El Khoury reported (33) that tPBM, by MRI, inhibited the default network, and Figueiro Longo et al. (31) and associates treated patients with traumatic brain injury and found in serial DTI studies that the active group but not sham had marked improvements at 3-months in their fiber pathways, through re-myelinization. Recent work suggests that a membrane opsin, TRPV1 (47) and extracellular TGF-beta1 (48) appear to be involved in the anti-inflammatory effects of photobiomodulation.
We chose F3 or F4 in our initial study in 2009 (24) and a subsequent study (49) because we hypothesized that the dorsolateral prefrontal cortex in each hemisphere might activate a broader area of the irradiated hemisphere and evoke an experiential change. Our primary aim was to activate the hemisphere with the more positive HEV as we did with our lateral visual field test (9, 11, 12, 15, 18, 19, 22, 23). Our strong clinical results (24, 49, 50) suggest that we might have chosen well. We have not tested fp1 or fp2, which we believe might be inhibitory.
Schiffer decided to explore whether using tPBM on the forehead over the more mature hemisphere might lead to improvements in opioid use disorder patients in his private practice. His very positive findings (51) led him to lead the design and performance of an initial double-blinded randomized control trial (RCT) (49), which reported statistically significant positive results with an effect size of 0.73, showing decreased opioid cravings in a within subject design in which 17 participants received an active or a sham treatment at week 1 and the opposite treatment at week 2.
The aim of the present study was to assess in a two-center RCT whether there would be a greater reduction in opioid craving over 4-weeks of twice weekly treatments with active vs. sham tPBM, and to compare the degree of efficacy in participants receiving or not receiving medication management. The primary outcome measure selected a priori were ratings on the opioid craving scale and the expectation was that there would be a reduction in opioid cravings of at least 60% in the active group vs. about a 20% decrease in the sham treatment group. We decided to examine opioid use during the study, even though active use was not a requirement for enrollment.