Ketamine for pain

Route of administration

Traditionally, ketamine has been administered via intravenous or intramuscular routes. However, alternative routes, such as oral, nasal, transdermal, subcutaneous, and rectal administration, have been described¹⁰. Recently, the administration of preservative-free ketamine by inhalation was tested successfully. Preservative-free ketamine inhalation allows the rapid and safe administration of the drug without the need for intravenous access¹¹. Ketamine inhalation seems useful under special circumstances such as palliative, geriatric, and preclinical emergency care as well as administration at remote locations such as the battlefield.

Metabolism

Ketamine undergoes extensive metabolism by liver cytochrome P450 enzymes. In humans, the major route of metabolism is N-demethylation to norketamine and subsequently cyclohexanone ring hydroxylation of norketamine to 4-, 5-, and 6-hydroxynorketamine⁹. All metabolic products are glucuronidated and cleared via kidney and bile. During long-term intravenous ketamine infusion, similar concentrations of norketamine and its parent compound are present, and following the termination of infusion, ketamine concentrations decrease rapidly but norketamine concentrations remain elevated above ketamine concentrations for hours. Experimental human studies suggest that in the treatment of acute pain, ketamine is the driving compound with little or no analgesic contribution from its metabolite norketamine¹². Preliminary modeling studies even suggest some algesic effects from norketamine¹². This may explain the observation of hyperalgesia and allodynia after long-term ketamine treatment in patients with neuropathic pain¹³.

Pharmacokinetics and pharmacodynamics

Ketamine is a lipophilic compound that easily crosses the blood-brain barrier. This results in a rapid onset of action of acute pain relief with an estimated blood–effect site equilibration half-life of close to 1 minute. Consequently, for this end-point, ketamine’s effect is driven by its pharmacokinetics through actions at NMDAR and mu-opioid receptor¹². For other end-points such as relief of neuropathic pain and depression, the onset and offset of ketamine are much slower with persistent effects at times when plasma concentrations of ketamine and its metabolites are reduced below detection levels. For example, we calculated a ketamine half-life for pain relief in patients with complex regional pain syndrome (CRPS) of 10.9 ± 4.0 days¹⁴. The slow onset/offset of ketamine in the treatment of chronic (neuropathic pain) may be explained by assuming that ketamine initiates a cascade of events, of which the effects persist beyond the treatment period. The initiating factor may be either the desensitization of the NMDAR or the activation of a receptor system that is involved in restoration of nociceptive homeostasis. We recently showed in rodents that activation of the innate repair receptor (IRR) by ketamine is a prerequisite for relief of neuropathic pain symptoms⁴. The IRR is a receptor complex composed of the erythropoietin receptor and the beta-common-receptor (CD131). Activation of the IRR results in tissue repair and anti-inflammation¹⁵. Endogenous activation is by erythropoietin (the natural anti-tumor necrosis factor cytokine), which is released upon tissue damage (for example, from ischemia, infection, and peripheral nerve damage). Of interest in this respect is the observation that in humans a selective peptide agonist of the IRR, ARA290 (Cibinetide™, Araim Pharmaceuticals, Inc.), produces effective and long-term relief of neuropathic symptoms in sarcoidosis patients with small fiber neuropathy, including the restoration of C-fibers in the cornea^16,17. A final mechanism through which ketamine induces pain relief is the reinforcement of the endogenous pain modulatory system by activation of descending inhibitory pathways involved in analgesia at the spinal level^18,19.

One major issue with the use of ketamine is the occurrence of side effects². Most important side effects include schizotypical effects (hallucinations, paranoia, derealization/depersonalization, and panic attacks), drug high, nausea/vomiting, and hypertension. These side effects can be present during administration but rapidly dissipate upon termination of treatment. Especially, the schizotypical effects limit patient (and doctor) compliance. However, at low-dose and/or by adding a benzodiazepine or an alpha-2-receptor agonist, the occurrence of side effects is limited and often well tolerated by the patient. Additionally, long-term use of ketamine is associated with tissue damage (for example, allergic hepatitis and hemorrhagic cystitis) and possibly also cognitive defects^2,20.

Ketamine effect in acute pain in an emergency or pre-hospital setting

We retrieved five systematic reviews^21–25 and present the results of the most recent one. Lee and Lee (2016) retrieved six randomized controlled trials (RCTs) involving 438 patients on the use of intravenous bolus ketamine versus placebo, morphine, or fentanyl in acute pain patients aged 15 years and older and treated in the emergency department²¹. The authors defined their primary end-point as change in pain intensity 30 minutes after treatment. The comparison of ketamine versus placebo did not reach the level of significance, although the need for rescue medication was less in studies comparing ketamine with placebo and fentanyl. Importantly, ketamine use was associated with a higher risk of neurological (relative risk (RR) 2.17, 95% confidence interval (CI) 1.37–3.42, P <0.001) and psychological (RR 1.36, 95% CI 4.9–29.6, P <0.001) events, whereas opioids were associated with a higher risk for cardiorespiratory events (RR 0.22, 95% CI 0.05–1.01, P = 0.05).

Ketamine for acute postoperative pain

We retrieved 14 unique reviews on ketamine or ketamine added to an opioid (for example, in a patient-controlled analgesia (PCA) device)^26–39. Three analyses were on ketamine for perioperative pain management in children, two of which were restricted to tonsillectomy. We discuss three meta-analyses:

(1) In their meta-analysis, Laskowski et al. (2011) included RCTs on intravenous ketamine for postoperative pain relief³⁶. They extracted 70 RCTs from the literature involving 4,701 patients. The authors performed a quantitative analysis on 47 of these studies. With ketamine (given before surgical incision, during surgery, or postoperatively), a significant reduction in total postoperative opioid use was observed (standardized difference in means (SDM) 0.63, 95% CI 0.46–0.80, P <0.001) with an increase in time to first analgesic rescue (SDM 0.95, 95% CI 0.55–1.26, P <0.001), indicative of the opioid-sparing effect of ketamine. Compared with the control group, ketamine-treated patients had more neuropsychiatric side effects (P = 0.018), decreased nausea and vomiting (P = 0.018), but no difference in sedation.

(2) The most recent (2016) high-quality meta-analysis on the effect of ketamine added to an opioid in a PCA device, by Assouline et al., included 19 RCTs from 1,349 adults and 104 children²⁷. The primary end-points were pain intensity at 24 hours, cumulative morphine consumption at 24 hours, postoperative nausea and vomiting, respiratory adverse events, and hallucinations. The authors’ analyses show that, with ketamine, pain scores were improved by about 1 cm on the 10 cm visual analogue scale (98% CI 0.4–1.8 cm, P <0.001; nine trials included), morphine consumption was reduced by about 13 mg (98% CI 3–22 mg, P = 0.002; seven trials included), and the incidence of nausea and vomiting was less with ketamine (RR 0.56, 98% CI 0.4–0.8, P <0.001; seven trials included). There were no differences in occurrence of respiratory events (data from nine trials) or hallucinations (data from seven trials) between patients treated with ketamine and those who were not.

(3) Dahmani et al. (2011) analyzed RCTs on ketamine for perioperative pain in children³⁵. The authors included 35 RCTs in their analysis. In 18 studies ketamine (or placebo) was administered intravenously (in 985 patients), in four studies ketamine was applied topically during a tonsillectomy (225 patients), and in 13 studies ketamine was given caudally as an adjuvant to opioid or local anesthetic caudal analgesia (714 patients). Following intravenous administration, ketamine reduced postoperative pain scores 2 hours after surgery (SDM −0.45, 95% CI −0.73 to −0.16) as well as postoperative analgesic medication (SDM 0.45, 95% CI 0.29–0.72). However, in the later postoperative period, 6–24 hours after surgery, none of the comparisons was significant, indicative of a short effect of ketamine. Ketamine was not associated with increased psychomimetic side effects or nausea/vomiting. Similar observations were made for topical application of ketamine during tonsillectomy. Ketamine as an adjuvant during caudal analgesia failed to affect early and later pain scores but did increase block duration (SDM 2.26, 95% CI 1.53–2.98) and reduced analgesic requirements postoperatively (SDM 0.26, 95% CI 0.10–0.66).

Ketamine for prevention of persistent postoperative pain

We retrieved two meta-analyses on this topic. Klatt et al. (2015)⁴⁰ identified 10 RCTs (784 patients) on the effect of intra- and postoperative intravenous ketamine on chronic pain after surgery. Three RCTs (303 patients) had a positive outcome, and the remaining seven showed no effect from ketamine on persistent pain. The meta-analysis revealed a small positive effect from ketamine on pain at rest 1 month after surgery (RR 0.52, 95% CI 0.27–0.97) but not for pain in motion (RR 0.79, 95% CI 0.53–1.16). No effect from ketamine was observed at 3, 6, or 12 months after surgery on pain at rest or in motion. McNicol et al. (2014)⁴¹ included all RCTs that administered ketamine by intravenous or epidural routes. The authors included 17 RCTs in 1,015 patients receiving ketamine and 785 placebo. The main end-pint was persistent pain at 3, 6, and 12 months. At 3 months, a non-significant RR of developing persistent pain was 0.84 with 95% CI 0.70–1.01 (P = 0.06) (that is, a non-significant 16% risk reduction). Overall, 28% of patients receiving ketamine versus 35% receiving placebo reported pain at 3 months postoperatively. Similar results were observed at 6 and 12 months.

Ketamine for chronic (non-cancer) pain

We retrieved five descriptive reviews on ketamine for chronic pain^20,42–45. All reviews were descriptive due to the heterogeneity between studies and poor-quality meta-analyses were not possible. In 2010, Noppers et al. retrieved 36 prospective RCTs on ketamine effect in chronic non-cancer pain involving 776 patients⁴⁴. Ketamine was used for a variety of conditions, including chronic neuropathic pain, peripheral nerve injury, complex regional pain syndrome, chronic migraine, limb ischemia, fibromyalgia, spinal cord injury, and whiplash. Most studies showed analgesic effects during ketamine administration, but just four studies showed analgesic efficacy lasting more than 48 hours. The latter four studies all employed ketamine infusions of at least 10 hours. Hence, as already concluded by Bell in 2009²⁰, ketamine can provide short-term pain relief in chronic pain. In addition, Noppers et al. concluded that long-term effects would require long-term infusion paradigms. It is important to realize that since 2010 just three RCTs on ketamine effect in chronic pain were published. They do not alter the current picture on efficacy of ketamine in chronic pain. All reviews highlight the occurrence of typical ketamine-related side effects.

Ketamine for cancer pain

We retrieved three unique systematic reviews on the use of ketamine for pain relief in patients with cancer^5,46,47. In all RCTs included in these reviews, ketamine was used as an adjuvant to opioid therapy. The latest and most complete review dates from 2017⁵. This review includes four RCTs in 245 patients who received oral, intravenous, or subcutaneous ketamine. Two studies on epidural or intrathecal ketamine were not included in the primary analysis. Three of the four trials involving over 90% of the study population reported a negative outcome, and the pain relief from ketamine in the fourth RCT lasted no longer than 3 hours. Additionally, all reviews reported ketamine-related side effects occurring in most patients.