Hyperbaric Oxygen Therapy for Pain, Opioid Withdrawal, and Related Symptoms: A Pilot Randomized Controlled Trial.

BACKGROUND: Pain, drug cravings, and opioid withdrawal symptoms can interfere with substance use disorder or opioid tapering treatment goals. AIM: This pilot study investigated the feasibility of a protocol designed to test opioid withdrawal symptom relief relative to a sham condition after two consecutive days of hyperbaric oxygen therapy (HBOT) for adults prescribed daily methadone for opioid use disorder. METHOD: Using a double-blind protocol, eight adults were randomized to receive either a full 90-minute HBOT dose in a pressurized chamber with 100% oxygen at 2.0 atmospheres absolute (ATA) or a sham condition receiving 21% oxygen (equivalent to room air within the chamber) at a minimal pressure of ≤1.3 ATA. Measures included study retention, treatment satisfaction, and pre- and post-intervention effects for opioid withdrawal symptoms, drug cravings, pain intensity and interference, sleep quality, and mood. RESULTS: Study retention and treatment satisfaction was high. All measurements improved more, on average, for participants receiving full-dose HBOT treatment than among participants receiving sham treatments except for clinically observed withdrawal symptoms. The largest positive effects were observed in measurements of pain intensity and drug craving. CONCLUSIONS: These pilot results provide evidence to support a fully powered study of HBOT as a potential treatment adjunct for adults receiving methadone for opioid use disorder. Trends towards symptom improvements were detected from pre- to post-HBOT in the full treatment arm versus sham condition. More research into novel non-pharmacologic options to relieve distressing symptoms related to pain and opioid use disorder is essential to improve clinical outcomes.

Hyperbaric Oxygen to Assist Adults With Opioid Use Disorder in Reducing Methadone Dose.

ABSTRACT: Opioid withdrawal symptoms can interfere with substance use disorder treatment goals. This study investigated the acceptability, feasibility, and treatment effects of hyperbaric oxygen therapy (HBOT) as an adjunct to reduce withdrawal symptoms for adults initiating a medically supervised methadone dose reduction. Adults prescribed methadone for opioid use disorder were randomized into either a hyperbaric oxygen group (n = 17) or an attention control group (n = 14). The study site was an outpatient opioid treatment program in the northwestern United States. Participants were asked to attend five consecutive daily 90-minute HBOT sessions offered at 2.0 atmospheres absolute with 100% oxygen in a pressurized chamber. Treatment attendance and reported satisfaction were measures of acceptability and feasibility. Medication doses were tracked posttreatment at 1 week, 1 month, and 3 months. Withdrawal symptoms were assessed at baseline and daily during the 5-day intervention period. After randomization, 13 (76.5%) followed through with medical screening and HBOT sessions, and of those, nine (69.2%) completed all five 90-minute HBOT sessions. At 3 months, the treatment group maintained, on average, a 4.3-mg methadone dose reduction compared with an average reduction of 0.25 mg for control group participants. Opioid withdrawal symptoms were reduced after Day 1 of HBOT by twice as much, on average, compared with the control condition. Satisfaction surveys found participants were generally satisfied with ease and comfort of the treatment. The evidence that HBOT is an acceptable, feasible adjunct warrants future trials to determine more conclusively effects on withdrawal symptoms associated with methadone dose taper.

Effect of hyperbaric oxygen on chemotherapy-induced neuropathy in male and female rats.

Chemotherapeutic agents can cause peripheral neuropathy, a deleterious side effect of cancer treatment. Hyperbaric oxygen (HBO2) treatment has shown great potential for decreasing pain in numerous clinical pain conditions and in preclinical studies. This study was designed to test whether HBO2 might also be useful for treating chemotherapy-induced peripheral neuropathy. Male and female Sprague-Dawley rats were injected with 1 mg/kg paclitaxel or vehicle every other day for 7 days to induce allodynia, followed by either one single, or four daily 60-min exposures to HBO2 or room air. Mechanical and cold allodynia as well as locomotor behavior and body weight were assessed intermittently for several weeks. Estrous cycling was also tracked in female rats. Paclitaxel caused pronounced mechanical allodynia in both sexes that was completely reversed by either one or four treatments of HBO2. Females in all treatment groups showed greater cold acetone scores than males, and acetone scores were not reliably reduced by HBO2 treatment. Neither paclitaxel nor HBO2 treatment altered locomotor behavior or estrous cycling. We conclude that HBO2 treatment was highly effective at reducing mechanical allodynia in paclitaxel-treated rats without affecting weight gain, locomotion, or estrous cycling, suggesting that HBO2 may be effective for treating chemotherapy-induced neuropathic pain without producing significant side effects.

Hyperbaric oxygen produces a nitric oxide synthase-regulated anti-allodynic effect in rats with paclitaxel-induced neuropathic pain.

Research has demonstrated that hyperbaric oxygen (HBO2) treatment produced relief of both acute and chronic pain in patients and animal models. However, the mechanism of HBO2 antinociceptive effect is still elusive. Based on our earlier findings that implicate NO in the acute antinociceptive effect of HBO2, the purpose of this study was to ascertain whether HBO2-induced antinociception in a chronic neuropathic pain model is likewise dependent on NO. Neuropathic pain was induced in male Sprague Dawley rats by four injections of paclitaxel (1.0 mg/kg, i.p.). Twenty-four hours after the last paclitaxel injection, rats were treated for one day or four consecutive days with 60-min HBO2 at 3.5 atmospheres absolute (ATA). Two days before HBO2 treatment, some groups of rats were implanted with Alzet® osmotic minipumps that continuously infused a selective inhibitor of neuronal NO synthase (nNOS) into the lateral cerebral ventricle for 7 days. Mechanical and cold allodynia were assessed every other day, using electronic von Frey and acetone assays, respectively. Rats in the paclitaxel control group exhibited a mechanical or cold allodynia that was significantly reversed by one HBO2 treatment for mechanical allodynia and four HBO2 treatments for cold allodynic. In rats treated with the nNOS inhibitor, the effects of HBO2 were nullified in the mechanical allodynia test but unaffected in the cold allodynia test. In summary, these results demonstrate that the antiallodynic effect of HBO2 in two different pain tests is dependent on NO in the CNS.

Role of spinal GABA receptors in the acute antinociceptive response of mice to hyperbaric oxygen.

New pain treatments are in demand due to the pervasive nature of pain conditions. Hyperbaric oxygen (HBO2) has shown potential in treating pain in both clinical and preclinical settings, although the mechanism of this effect is still unknown. The aim of this study was to investigate whether the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) is involved in HBO2-induced antinociception in the central nervous system (CNS). To accomplish this goal, pharmacological interactions between GABA drugs and HBO2 were investigated using the behavioral acetic acid abdominal constriction test. Western blotting was used to quantify protein changes that might occur as a result of the interactions. GABAA but not GABAB receptor antagonists dose-dependently reduced HBO2 antinociception, while antagonism of the GABA reuptake transporter enhanced this effect. Western blot results showed an interaction between the pain stimulus and HBO2 on expression of the phosphorylated ß3 subunit of the GABAA receptor at S408/409 in homogenates of the lumbar but not thoracic spinal cord. A significant interaction was also found in neuronal nitric oxide synthase (nNOS) expression in the lumbar but not thoracic spinal cord. These findings support the notion that GABA may be involved in HBO2-induced antinociception at the GABAA receptor but indicate that more study will be needed to understand the intricacies of this interaction.

Hyperbaric oxygen treatment suppresses withdrawal signs in morphine-dependent mice.

Hyperbaric oxygen (HBO2) therapy reportedly reduces opiate withdrawal in human subjects. The purpose of this research was to determine whether HBO2 treatment could suppress physical signs of withdrawal in opiate-dependent mice. Male NIH Swiss mice were injected s.c. with morphine sulfate twice a day for 4 days, the daily dose gradually increasing from 50mg/kg on day 1 to 125mg/kg on day 4. On day 5, withdrawal was precipitated by i.p. injection of 5.0mg/kg naloxone. Mice were observed for physical withdrawal signs, including jumping, forepaw tremor, wet-dog shakes, rearing and defecation for 30min. Sixty min prior to the naloxone injection, different groups of mice received either a 30-min or 60-min HBO2 treatment at 3.5atm absolute. HBO2 treatment significantly reduced naloxone-precipitated jumping, forepaw tremor, wet-dog shakes, rearing and defecation. Based on these experimental findings, we concluded that treatment with HBO2 can suppress physical signs of withdrawal syndrome in morphine-dependent mice.

The acute antinociceptive effect of hyperbaric oxygen is not accompanied by an increase in markers of oxidative stress.

AIMS: Exposure to hyperbaric oxygen (HBO2) causes an antinociceptive response in mice. However, breathing oxygen (O2) at an elevated pressure can potentially cause oxygen toxicity. The aim of this study was to identify the determinants of HBO2 antinociception and the toxicity profile of HBO2. MAIN METHODS: Male NIH Swiss mice were assessed for acute antinociceptive responsiveness under room air or 100% O2 at 1.0 or 3.5 atmospheres absolute (ATA), using the acetic acid-induced abdominal constriction test. For the oxygen toxicity test, mice were exposed to 3.5 ATA oxygen for 11min, 60min, and 60min daily for 2days (120min) or 60min daily for 4days (240min), then assessed by analyzing the levels of two oxidative stress markers, MDA (malondialdehyde) and protein carbonyl in brain, spinal cord and lung. KEY FINDINGS: Only the combination of 100% O2 and 3.5 ATA caused significant antinociception. The antinociceptive effect of 100% O2 was pressure-dependent up to 3.5 ATA. In the oxygen toxicity test, mice exposed to HBO2 for different time intervals had levels of brain, spinal cord and lung MDA and protein carbonyl that were comparable to that of control animals exposed to room air. SIGNIFICANCE: Treatment with 100% O2 evokes a pressure-dependent antinociceptive effect. Since there was no significant increase in levels of the oxidative stress markers in the tested tissues, it is concluded that HBO2 at 3.5 ATA produces antinociception in the absence of oxidative stress in mice.

Involvement of spinal cord opioid mechanisms in the acute antinociceptive effect of hyperbaric oxygen in mice.

Earlier research has demonstrated that treatment with hyperbaric oxygen (HBO2) can elicit an antinociceptive response in models of acute pain. We have demonstrated that this antinociceptive effect is centrally-mediated and is dependent on opioid receptors. The purpose of the present study was to examine the role of endogenous opioid peptides and opioid receptors specifically in the spinal cord in the acute antinociceptive effect of HBO2 in mice. Male NIH Swiss mice were exposed to HBO2 (100% oxygen at 3.5atm absolute) for 11min and their antinociceptive responsiveness was determined using the glacial acetic acid-induced abdominal constriction test. HBO2-induced antinociception was sensitive to antagonism by intrathecal (i.t.) pretreatment with the κ- and µ-selective opioid antagonists norbinaltorphimine and ß-funaltrexamine, respectively, but not the δ-selective antagonist naltrindole. The antinociceptive effect of HBO2 was also significantly attenuated by i.t. pretreatment with a rabbit antiserum against rat dynorphin1-13 but not antisera against ß-endorphin or methionine-enkephalin. Based on these experimental findings, the acute antinociceptive effect of HBO2 appears to involve neuronal release of dynorphin and activation of κ- and µ-opioid receptors in the spinal cord.

Involvement of brain opioid receptors in the anti-allodynic effect of hyperbaric oxygen in rats with sciatic nerve crush-induced neuropathic pain.

Earlier research has demonstrated that hyperbaric oxygen (HBO2) can produce an antinociceptive effect in models of acute pain. Recent studies have revealed that HBO2 can produce pain relief in animal models of chronic pain as well. The purpose of the present investigation was to ascertain whether HBO2 treatment might suppress allodynia in rats with neuropathic pain and whether this effect might be blocked by the opioid antagonist naltrexone (NTX). Male Sprague Dawley rats were subjected to a sciatic nerve crush under anesthesia and mechanical thresholds were assessed using an electronic von Frey anesthesiometer. The time course of the HBO2-induced anti-allodynic effect in different treatment groups was plotted, and the area-under-the-curve (AUC) was determined for each group. Seven days after the nerve crush procedure, rats were treated with HBO2 at 3.5 atm absolute (ATA) for 60 min and exhibited an anti-allodynic effect, compared to nerve crush-only control rats. Twenty-four hours before HBO2 treatment, another group of rats was implanted with Alzet(®) osmotic minipumps that continuously released NTX into the lateral cerebral ventricle for 7 days. These NTX-infused, HBO2-treated rats exhibited an allodynic response comparable to that exhibited by rats receiving nerve crush only. Analysis of the AUC data showed that HBO2 significantly reduced the nerve crush-induced allodynia; this anti-allodynic effect of HBO2 was reversed by NTX. These results implicate opioid receptors in the pain relief induced by HBO2.

An anxiolytic-like effect of hyperbaric oxygen in the mouse light/dark exploration test.

AIMS: We studied whether hyperbaric oxygen (HBO(2)) treatment, which is known to increase production of nitric oxide (NO) in the brain, might also produce an NO-dependent anxiolytic-like behavioral response. MAIN METHODS: Male NIH Swiss mice (20-25g) were subjected to a 60-min HBO(2) treatment at different absolute atmospheres, and anxiety was assessed using the light/dark exploration test at different time intervals following the cessation of HBO(2) treatment. To ascertain the underlying mechanism of action, other groups of mice were pretreated with the NO synthase inhibitor N(G)-monomethyl-l-arginine acetate, the NO scavenger 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3-oxide (carboxy-PTIO), the soluble guanylyl cyclase-inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) or the benzodiazepine antagonist flumazenil to determine their influence on the HBO(2)-induced anxiolytic-like effect. KEY FINDINGS: A 60-min HBO(2) treatment at 3.0 absolute atmospheres increased the time spent by mice in the light compartment that lasted up to 90 min following the end of HBO(2) treatment. This anxiolytic effect of HBO(2) was significantly reduced by pretreatment with L-NMMA, carboxy-PTIO, ODQ and flumazenil. SIGNIFICANCE: Based on these findings, we conclude that a 60-min HBO(2) treatment is capable of inducing an anxiolytic effect that possibly involves NO, cyclic GMP and the benzodiazepine binding site.

The acute antinociceptive effect of HBO2 is mediated by a NO-cyclic GMP-PKG-KATP channel pathway in mice.

Previous research has found that hyperbaric oxygen (HBO(2)) produces an acute antinociceptive effect that is dependent on nitric oxide (NO). The present study was undertaken to determine whether HBO(2)-induced acute antinociception might involve a NO-cyclic GMP-protein kinase G-ATP-sensitive potassium (K(ATP)) channel pathway. Male NIH Swiss mice were subjected to a 5-min HBO(2) treatment (100% oxygen at 3.5 absolute atmospheres) and antinociception was assessed over the next 6 min still under HBO(2) using the acetic acid abdominal constriction test. Pretreatment with 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3-oxide (carboxy-PTIO, an NO scavenger), 1H-[1,2,4]-oxadiazolo-[4,3-a]quinoxalin-1-one) (a soluble guanylyl cyclase-inhibitor, Rp-8-(4-chlorophenylthio)-guanosine-3',5'-cyclic monophosphorothioate (a protein kinase G-inhibitor) or glibenclamide (an ATP-sensitive potassium channel-inhibitor) all led to antagonism of the HBO(2)-induced acute antinociception in a dose-dependent manner. These findings suggest that HBO(2)-induced acute antinociception might be due to activation of a NO-cyclic GMP-protein kinase G-K(ATP) channel pathway.

Effect of hyperbaric oxygen on the anticancer effect of artemisinin on molt-4 human leukemia cells.

BACKGROUND: Artemisinin selectively kills cancer cells which have more intracellular free iron than do normal cells. Hyperbaric oxygen (HBO(2)) may be beneficial in the treatment of cancer. The hypothesis of this study was that HBO(2) enhances anticancer activity of artemisinin. MATERIALS AND METHODS: After pretreatment with 12 µM holotransferrin, Molt-4 human leukemia cells were cultured in 10 µM artemisinin and exposed for 90 min to one of three different conditions: control, room air control, and HBO(2). Cell growth was determined for 48 h after exposure. RESULTS: Differences in growth were noted after 6 h of incubation. After 48 h of incubation, growth of cells treated with artemisinin alone or HBO(2) alone was 85% of that of cells grown under artemisinin-free control conditions. Combined artemisinin and HBO(2) treatment resulted in an additional 22% decrease in growth. CONCLUSION: Combined HBO(2) and artemisinin exposure may be an effective anticancer chemotherapeutic strategy.

Hyperbaric oxygen treatment induces a 2-phase antinociceptive response of unusually long duration in mice.

UNLABELLED: Hyperbaric oxygen (HBO(2)) therapy is approved by the FDA for limited clinical indications but is reported to produce pain relief in several chronic pain conditions. However, there have been no studies to explain this apparent analgesic effect of HBO(2). Research conducted in our laboratory demonstrates that 4 daily 60-minute HBO(2) treatments at 3.5 absolute atmospheres induced an unparalleled antinociceptive response that consists of 1) an early phase that lasted at least 6 hours after the HBO(2) treatment before dissipating; and 2) a late phase that emerged about 18 hours after the early phase and lasted for up to 3 weeks. The early phase was sensitive to antagonism by acutely intracerebroventricular (i.c.v.)-administered opioid antagonist naltrexone and the nitric oxide synthase (NOS)-inhibitor L-NAME. The late phase was inhibited by treatment with i.c.v. naltrexone or L-NAME during the 4 daily HBO(2) treatments but was not antagonized by either naltrexone or L-NAME following acute pretreatment 2 weeks after HBO(2) treatment. These experimental results implicate a novel mechanism that is activated by HBO(2), resulting in an antinociceptive response of unusually long duration that is of potential interest in the clinical management of pain. PERSPECTIVE: Hyperbaric oxygen treatment of mice can induce a 2-phase antinociceptive response of unusually long duration. Nitric oxide and opioid receptors appear to initiate or mediate both phases of the antinociceptive response. Further elucidation of the underlying mechanism may potentially identify molecular targets that cause long-lasting activation of endogenous analgesic systems.

Nitric oxide in hyperbaric oxygen-induced acute antinociception in mice.

Hyperbaric oxygen (HBO2) therapy induces analgesia in various conditions of pain in humans. In mice, HBO2 treatment evokes an acute antinociceptive response in the abdominal constriction test. To demonstrate the dependence of HBO2-induced antinociception on nitric oxide (NO), antinociceptive responsiveness to HBO2 was assessed after three different approaches that interfered with NO production. HBO2-induced antinociception was significantly attenuated by intracerebroventricular and intrathecal pretreatment with an inhibitor of NO synthase (NOS) enzyme and also by an antisense oligodeoxynucleotide directed against neuronal NOS. The antinociceptive effect was also significantly reduced in mice homozygous for a defective neuronal NOS gene. On the basis of these results, we conclude that neuronal NO is critical in the expression of the acute antinociceptive effect of HBO2.

A prolonged nitric oxide-dependent, opioid-mediated antinociceptive effect of hyperbaric oxygen in mice.

UNLABELLED: Hyperbaric oxygen (HBO(2)) therapy is reported to cause pain relief in several conditions of chronic pain. A single 60-minute session of HBO(2) treatment produced a prolonged antinociceptive effect in mice that persisted for 90 minutes after cessation of treatment. The HBO(2)-induced antinociception was significantly attenuated by pretreatment before HBO(2) exposure with the opioid antagonist naltrexone, the nonspecific nitric oxide synthase (NOS)-inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME), and the selective neuronal NOS-inhibitor S-methyl-L-thiocitrulline (SMTC) but not the selective endothelial NOS-inhibitor N(5)-(1-iminoethyl)-L-ornithine (L-NIO). The antinociception was also significantly reduced by central pretreatment with a rabbit antiserum against dynorphin(1-13) but not by rabbit antisera against either beta-endorphin or methionine-enkephalin. The prolonged antinociceptive effect at 90 minutes after HBO(2)-induced treatment was also significantly attenuated by naltrexone but not L-NAME administered 60 minutes after HBO(2) treatment but before nociceptive testing. These findings indicate that the antinociception that persists for 90 minutes after HBO(2) exposure is mediated by nitric oxide (NO) and opioid mechanisms but that the NO involvement is critical during the HBO(2) treatment and not at the time of nociceptive testing. These results are consistent with the concept that HBO(2) may induce an NO-dependent release of opioid peptide to cause a long-acting antinociceptive effect. PERSPECTIVE: This article presents evidence of a persistent antinociceptive effect of hyperbaric oxygen treatment that is mediated by opioid and NO mechanisms. Further elucidation of the underlying mechanism could identify molecular targets to cause a longer-acting activation of endogenous pain-modulating systems.

The effect of hyperbaric oxygen on regional brain and spinal cord levels of nitric oxide metabolites in rat.

Hyperbaric oxygen (HBO(2)) therapy is reported to be beneficial in transient brain ischemia. The present study was conducted to determine the influence of HBO(2) on metabolites of nitric oxide (NO) in brain and spinal cord of rats. Rats were exposed to room air (RA), normobaric air (NBA), normobaric oxygen (NBO(2)), hyperbaric air (HBA) or HBO(2), the last two conditions at 2.5ATA (atmosphere absolute) for 60 min. The results demonstrate that, compared to the NBA control, oxygen alone generally reduced tissue levels of NO(x)(-) (nitrite plus nitrate). On the other hand, 2.5ATA alone tended to have a slight, if any, effect on tissue levels of NO(x)(-). The combination of oxygen and pressure (i.e., HBO(2)) generally led to an increase in tissue levels of NO(x)(-). Based on these findings, it is concluded that HBO(2) appears to markedly increase NO function most notably in the corpus striatum, brainstem, cerebellum and spinal cord.

A study of the role of serotonin in the anxiolytic effect of nitrous oxide in rodents.

RATIONALE: In earlier studies, we have shown that nitrous oxide (N2O)-induced behavioral effects in rats and mice are mediated by benzodiazepine receptors. OBJECTIVES: This two-part study was conducted in order to investigate the possible role of serotonin (5-HT) in the behavioral effects of N2O by clarifying its effects on regional brain concentrations of 5-HT and assessing the influence of 5-HT antagonist and reuptake inhibiting drugs on the anxiolytic-like behavioral effect of N2O. METHODS: In experiment A, male, 150-200 g Sprague-Dawley rats were killed following a 15-min exposure to room air or 70% N2O. The frontal cortex, hippocampus, corpus striatum and hypothalamus were dissected out and analyzed by HPLC with electrochemical detection for content of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA); dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) were also measured. In experiment B, male 18-22 g NIH Swiss mice were pretreated with the 5-HT2 antagonist cinanserin, the 5-HT3 antagonist LY-278,584, the 5-HT reuptake inhibitor fluoxetine or saline and tested in the light/dark exploration test under 70% N2O 30 min after pretreatment. RESULTS: In experiment A, N2O produced differential effects on 5-HT neurons in distinct brain areas. There was increased 5-HT turnover in the hypothalamus, decreased turnover in the frontal cortex but no changes in either hippocampus or corpus striatum. By comparison, dopamine turnover in these brain regions was unaltered by N2O exposure. In experiment B, pretreatment with neither cinanserin, LY-278,584 nor fluoxetine had any appreciable effect on the N2O-induced increase in time spent in the light compartment. Only cinanserin significantly reduced the N2O-induced increase in transitions. CONCLUSIONS: While neurochemical results suggest an effect of N2O on brain 5-HT function, there was no effect of 5-HT2 or 5-HT3 antagonists or 5-HT reuptake inhibitor on N2O-induced anxiolytic-like behavior.