Evidence Review Questions Ketamine’s Role In Chronic Pain Treatment

Despite increasing off-label use, ketamine and related NMDA blockers show nary reliable grounds of easing chronic pain, highlighting nan urgent request for safer and much effective treatments.

Review: Ketamine and different NMDA receptor antagonists for chronic pain. Image Credit: ANDREI ASKIRKA  / Shutterstock

In a reappraisal published successful the Cochrane Database of Systematic Reviews, researchers examined nan benefits and adverse effects of ketamine and different NMDA receptor antagonists, compared to a placebo, utilized to dainty adults pinch chronic non-cancer, non-headache pain.

Chronic Pain: Prevalence and Symptoms

Chronic pain is simply a type of symptom that persists for 3 months aliases more, affecting astir 20% of adults successful nan US, 19% successful Europe, and 33% successful low- and middle-income countries. Many communal chronic symptom conditions see little backmost pain, osteoarthritis, and cervix pain. Many studies person shown that chronic symptom negatively affects mood, expertise to work, and societal participation.

A caller study estimated that nan economical load arising from chronic symptom successful nan USA and Australia has been estimated astatine USD 560-635 cardinal and AUD 139 cardinal per year, respectively.

In 2019, nan World Health Organization (WHO) revised nan classification of chronic pain, formally separating chronic superior symptom from chronic secondary pain. Chronic superior symptom occurs persistently and has been associated pinch affectional distress and disablement that cannot beryllium accounted for by different condition. In contrast, chronic secondary symptom initially occurs arsenic a denotation secondary to an identifiable underlying illness aliases condition, specified arsenic neuropathic pain.

Investigated Treatments: NMDA Receptor Antagonists

The reappraisal focused connected NMDA receptor antagonists - a group of narcotics whose underlying system of action is nan inhibition of nan NMDA receptor, a commonly recovered glutamate-gated ion transmission that facilitates excitatory neurotransmission. These see ketamine, memantine, dextromethorphan, amantadine, and magnesium.

Ketamine is simply a type of non-competitive NMDA receptor antagonist, which acts arsenic an anesthetic astatine higher dosages and arsenic an analgesic and sedative astatine little dosages. Clinicians sometimes prescribe off-label intravenous aliases oral ketamine to dainty chronic symptom contempt uncertain benefits and harms. Multiple studies person shown that this supplier has a accelerated plasma half‐life of astir 2.3 hours. It undergoes oxidative hepatic metabolism done cytochrome P450 CYP3A4 and CYP2B6 enzymes to norketamine, its progressive metabolite. It must beryllium noted that nan higher first‐pass metabolism of ketamine via CYP3A4 enzymes makes it susceptible to interactions pinch different drugs, mostly opioids and benzodiazepines.

In summation to psychotomimetic effects, ketamine management is besides associated pinch nausea, vomiting, and hypersalivation. Previous studies person highlighted nan consequence of dependence, addiction, and withdrawal effects linked pinch ketamine. The reappraisal emphasized that high-quality information information stay lacking.

About nan Review

Although ketamine and different NMDA receptor antagonists are progressively utilized for chronic symptom treatment, nary reviews are disposable successful nan Cochrane Library that assessed nan benefits and broadside effects of these drugs. An up-to-date reappraisal will thief clinicians and policymakers to create and instrumentality effective curen guidelines.

The existent reappraisal included studies connected mixed symptom populations, randomized controlled tests (RCTs), while excluding studies of crab aliases headache pain. Non‐randomised studies, lawsuit reports, objective observations, and experimental studies utilizing symptom induction were excluded. Studies that included adults aged 18 years and older reporting chronic symptom of astatine slightest 3 months' long were included. Individuals' symptom strength scores were measured utilizing a ocular analogue standard (VAS), a verbal standing scale, a numeric standing standard (NRS), a Likert scale, aliases an ordinal scale.

Review Findings

A full of 15,759 articles were initially identified from different databases. After removing duplicates, nan qualitative synthesis included 67 studies, and nan quantitative synthesis (meta-analysis of symptom strength and adverse events) included 28 studies. The 67 selected studies had randomized 2,309 participants, whose symptoms ranged from neuropathic pain, fibromyalgia, and analyzable location symptom syndrome. Approximately 58% of studies were excluded from quantitative syntheses owed to unavailable first-phase information from crossover tests aliases result measurements ≤48 hours.

Most studies indicated nan intravenous way of ketamine management and analyzed its effect by comparing it pinch placebo treatment. No clear grounds indicated that intravenous ketamine reduces symptom strength astatine immediate‐, short‐, aliases medium‐term follow‐up. The assurance intervals were wide, showing imaginable clinically important effects aliases nary effect. Intravenous ketamine whitethorn summation nan consequence of adverse effects, specified arsenic nausea, psychotomimetic effects, and vomiting. Subgroup analyses did not uncover immoderate differences successful intravenous ketamine effects based connected objective information aliases long of curen administration.

No formulation of ketamine (intravenous, oral, aliases topical) showed clear benefits for symptom relief. Based connected nan study findings, grounds for oral and topical ketamine was inconclusive owed to minimal information from mini studies. Six studies evaluated the efficacy of oral memantine against a placebo, showing nary clear grounds that this involution reduces symptom strength astatine immediate-, short-, aliases medium-term follow-up.

The subgroup study revealed that nan effects of oral memantine mightiness alteration depending connected nan objective condition. However, this study had debased statistical powerfulness and requires cautious interpretation. Memantine curen showed nary evident summation successful consequence for nausea, sedation, dizziness, aliases headache. For astir NMDA antagonists, grounds connected adverse events was minimal and uncertain.

The authors recovered inconclusive grounds for oral dextromethorphan, amantadine, and magnesium (administered intravenously, orally, aliases intramuscularly) owed to a constricted number of mini studies pinch imprecise estimates.

Conclusions

The existent reappraisal highlighted very limited, low-to-very low-certainty grounds connected nan effects of each studied NMDA receptor antagonists connected symptom intensity. Although intravenous ketamine curen was recovered to summation nan consequence of adverse effects potentially, nan grounds for different formulations and NMDA antagonists remained unclear. Critically, nan authors concluded: "Current grounds is insufficient to pass objective practice."

In nan future, adequately powered RCTs are required to find nan efficacy and information of ketamine and different NMDA receptor antagonists for chronic symptom management.