Ketamine Infusions for Chronic Pain

A Systematic Review and Meta-analysis of Randomized Controlled Trials

Vwaire Orhurhu, MD, MPH; Mariam Salisu Orhurhu, MD, MPH; Anuj Bhatia, MD, FRCPC; Steven P. Cohen, MD

Disclosures

Anesth Analg. 2019;129(1):241-254. 

In This Article

Discussion

This systematic review and meta-analysis of 7 randomized control trials evaluated persistent analgesic efficacy from IV ketamine infusions versus placebo for chronic pain. It reveals that IV ketamine is effective for a wide array of chronic pain conditions, although the benefits dissipate with time. Use of IV ketamine resulted in a reduction in pain scores between 48 hours and 2 and 8 weeks after the infusion, but the pooled difference in pain reduction at 4 weeks fell shy of significance. The incidence of nausea and vomiting with IV ketamine was higher than with placebo.

A recently published systematic review and meta-analysis that investigated ketamine for chronic pain included non-IV routes of administration,[4] while another limited the study cohort to participants with complex regional pain syndrome.[33] The review by Michelet et al[4] found no analgesic efficacy with ketamine at 4 weeks, but paradoxically some benefit at 12 weeks, which is a function of methodology that failed to account for differences in follow-up (ie, negative studies at 4 weeks were not considered negative evidence at 12 weeks).[4] It is hypothesized that reversing wind-up and central sensitization require high-concentration bombardment and blockade of NMDA receptors, which are intimately involved in neuroplasticity.[34] Consequently, extremely low-dose transdermal administration or intermittent blockade with "as needed" oral ketamine, which has a very low bioavailability of 8%–24%,[35] is unlikely to accomplish this goal. This fact, along with the widespread interest in IV administration among patients and caregivers, led us to include only studies that examined outcomes after IV administration.

Analgesic Outcomes

The randomized control trials included in our analysis used diverse pain scales that were often presented in ways that made accurate extraction of raw data difficult. Hence, the results in some studies were standardized during quantitative analysis. The challenges imposed by heterogeneity of outcomes in the pain literature[36] have compelled authors of systematic reviews to adopt a "best available evidence approach."[37–39] The conclusions from our meta-analysis examining maximum pain relief should be interpreted with caution because they are based only on 6 small studies. Furthermore, the heterogeneity in time points used for analgesic assessment poses a challenge in evaluating duration of benefit of ketamine infusions.

Analgesic Effect of Ketamine in Different Pain Syndromes

The randomized control trials evaluated in this review included neuropathic, mixed nociceptive and neuropathic pain (eg, spinal cord injury, phantom limb pain, cancer, complex regional pain syndrome types I and II),[24–27] and nociceptive (eg, ischemic limb pain)[29] or nociplastic pain syndromes (eg, complex regional pain syndrome type I and fibromyalgia).[23,28] In subgroup analysis, we found no evidence for superior analgesic benefit from ketamine in neuropathic compared to nociceptive or nociplastic pain syndromes. The same held true for a comparison between non–complex regional pain syndrome and complex regional pain syndrome populations. Some may consider this surprising considering that ketamine has been better studied in neuropathic pain models. It is worth noting that, although not significant, the magnitude of reduction in pain scores was greater among complex regional pain syndrome subgroups, indicating a need for larger and more methodologically robust trials. The International Association for the Study of Pain defines neuropathic pain as "pain caused by a lesion or disease of the somatosensory nervous system."[40] This definition excludes conditions characterized by central sensitization in the absence of a discrete nerve injury, such as complex regional pain syndrome type I and fibromyalgia.[40] More recently, a third pain descriptor, nociplastic, has been introduced to classify conditions associated with altered processing of pain that do not conform to the nociceptive category. Examples of nociplastic pain include fibromyalgia, complex regional pain syndrome, nonspecific chronic low-back pain, irritable bowel syndrome, and other "functional" visceral pain disorders.[41] However, ketamine's primary analgesic effect remains ambiguous because it is purported to work by either dampening of CNS pain amplification via numerous pathways and/or reversal of central sensitization by NMDA receptor blockade.[34] Whereas the preclinical evidence supporting ketamine is strongest for neuropathic pain, there is a growing body of evidence demonstrating antinociceptive and analgesic effects in inflammatory and other nociceptive as well as nociplastic pain conditions, including headaches.[42,43] Whether differences in analgesic effects are due to actual differences in efficacy or a byproduct of methodological differences are areas ripe for further research.

We included studies that evaluated ketamine as add-on therapy for neuropathic and nociceptive or nociplastic pain, which reflects clinical practice. For cancer, the World Health Organization analgesic stepladder recommends adding adjuvants to existing therapy, not as a replacement,[44] and ketamine is not considered a first-line agent for neuropathic pain, but it is typically used as a rescue agent.[45] Reviews have also found that combination therapy is superior to single-agent therapy for chronic pain syndromes.[46] In the recently published guidelines on IV ketamine for acute pain, one of the questions addressed is whether there is any benefit to adding ketamine to opioid therapy, which was answered affirmatively.[47]

Dose–response Effect of Ketamine

We found evidence for higher dosages to be associated with greater and longer pain relief, which is not surprising because nearly all analgesic medications are associated with a dose–response effect. However, our analysis may not have shown statistical significance because of the small number of studies in our subgroup analysis. We found that IV ketamine is associated with a significantly higher incidence of nausea and vomiting compared to placebo. However, the data were insufficient to determine the cause–effect relationship between adverse effects and discontinuation of IV ketamine. A previous retrospective study found that discontinuation of IV ketamine secondary to side effects was unrelated to maximum infusion rate.[48] This may be a function of the relatively low incidence of certain adverse effects and flaws in surveillance methods. In 1 review,[49] as well as in the consensus guidelines on the use of ketamine in chronic pain,[3] the authors concluded that higher dosages are associated with better analgesia, although studies correlating blood levels with pain relief have yielded mixed results.[24,50–52] Variables that may affect the therapeutic dose range include underlying pathology, previous exposure to ketamine and comedications.

Challenges With Blinding Participants in Studies Evaluating Ketamine

Although all studies included in our review were ostensibly double-blinded, 83% of participants allocated to ketamine correctly guessed treatment in the 2 studies in which blinding was assessed.[24,26] Studies have found that ineffective blinding may augment the treatment effect by between 15% and 25%.[53–55] Although it is challenging to ensure effective blinding when the medication of interest is associated with unique psychotropic effects, the expectations associated with receiving therapy play an integral role in treatment response,[56] and steps can be taken to reduce bias when blinding is not feasible.[57]

Limitations of Current Evidence

There are several limitations to this review including the small number of patients enrolled in trials (median sample size of 24 participants), which may be attributed to the lack of industry funding for a generic medication, and the lack of standardization for infusion regimens, patient selection, and follow-up periods. In general, studies for medications that receive Food and Drug Administration approval go through a well-defined process that includes determining the optimal dose via phase I and II clinical trials, followed by large-scale randomized trials with stringent selection criteria that typically assess participants for 12 weeks. In contrast, the studies in this review treated small number of patients with refractory pain using myriad dose regimens, and often failed to include secondary outcomes or evaluate intermediate-term effects. Clinical heterogeneity in the studies included in this review was a significant challenge we attempted to explore but were unable to identify causes. In addition, the difference in effect size required to detect a statistically significant improvement in pain score may not fully reflect the true clinical effect. For example, the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) guidelines note, "… in evaluating a new analgesic, if a 2-point decrease on a 0 to 10 numerical rating scale of pain intensity is considered a clinically important improvement for an individual, it should not be inferred that a 2-point difference in pain reduction between the analgesic and placebo must occur before the treatment benefit can be considered clinically important."[58] Due to the subjectivity of reported pain scores among patients, wide variations in response, and high placebo response rates, the clinical relevance of the differences in effect size is hard to determine. Finally, chronic pain management includes not only the reduction of pain but also improved quality of life, which should be measured via validated instruments.[59] Unfortunately, our analysis could not account for these outcomes due to limited availability of outcome data.

Recommendations and Conclusions

Based on the quality of the evidence from studies in this review and the strength of effect, it is recommended that IV ketamine be used, on a case-by-case basis, as a primary analgesic in patients with chronic pain refractory to more conventional treatments (GRADE: weak recommendation; low evidence)[22] (Table 2). However, our confidence in this analgesic effect is limited and the actual effect of IV ketamine among chronic pain patients may vary widely. IV ketamine may be associated with improvement in pain scores observed during the infusion, quantified as early as 48 hours after the infusion, and lasting for ≥2 weeks when high-dose regimens are used. Whereas reductions in pain scores were observed with a range of dosages, more robust analgesic effects were observed with higher dosages. Further research should seek to determine the ideal patients and conditions for this treatment, the optimal dosing regimen, whether combination therapy with ketamine provides superior benefit than stand-alone treatment, the impact of infusions on physical and psychological functioning, and long-term adverse effects.

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