Year : 2020 | Volume
: 34 | Issue : 1 | Page : 3--7
Central sensitization and its role in chronic pain: What can ketamine do?
Vinita Singh, Jack Williams Shteamer, Jonathan Seth Lowe, Mayson Callaway Augustus
Department of Anesthesia, Emory University, Atlanta, GA, USA
Dr. Vinita Singh
1364 Clifton Rd, Emory University Hospital, Atlanta, 30322, GA
Central sensitization plays a crucial role in the development of chronic pain. NMDA receptors play a key role in central sensitization. Ketamine, an NMDA receptor antagonist, can help in refractory chronic pain. Although intravenous is the most common route utilized for delivery of ketamine, other routes such as oral, subcutaneous, topical and intranasal, have been explored. Here we review key research articles regarding the use of ketamine for chronic pain.
|How to cite this article:|
Singh V, Shteamer JW, Lowe JS, Augustus MC. Central sensitization and its role in chronic pain: What can ketamine do?.Indian J Pain 2020;34:3-7
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Singh V, Shteamer JW, Lowe JS, Augustus MC. Central sensitization and its role in chronic pain: What can ketamine do?. Indian J Pain [serial online] 2020 [cited 2020 May 31 ];34:3-7
Available from: http://www.indianjpain.org/text.asp?2020/34/1/3/282546
Chronic pain can have many sources, and the treatment of a patient's pain depends heavily upon the source of the pain. Central sensitization is a key concept in understanding why patients are hurting in seemingly normal situations. With central sensitization, neuroplastic changes occur, allowing aberrant signals to be transmitted, giving the patient the sensation of pain to nonnoxious stimuli. This can occur via chronic peripheral nerve damage releasing pro-inflammatory mediators and by redistribution of sodium and calcium channels, resulting in spontaneous firing and functional changes in the dorsal horn. In this pathological state, the glial cells release glutamate, an N-methyl D-aspartate (NMDA) receptor agonist. NMDA antagonism can result in analgesia by preventing the central sensitization in these dorsal horn nuclei.
Ketamine is frequently used in the emergency room, operating room, and intensive care unit for procedural sedation and induction of anesthesia and is used as an adjunct in the treatment and prevention of perioperative pain. It exerts its primary action at the NMDA receptor, where it functions as an antagonist at the phencyclidine receptor. The ketamine molecule binds to the receptor in the open state, reducing the frequency of channel opening and time spent in the open state. The NMDA receptor has been correlated to the development of chronic pain, opioid tolerance, hyperalgesia, mood regulation, central sensitization, and windup.,,, In an animal model, ketamine was shown to decrease opioid-induced hyperalgesia and opioid tolerance, while in humans, it has been shown to potentiate the analgesic effects and duration of opioids. The effects of ketamine are not only realized at the NMDA receptor but it also acts at several other receptors in the brain, including GABA receptors, dopamine receptors, calcium channels, modulation of cholinergic neurotransmission, and inhibition of serotonin and norepinephrine reuptake. Its effect on metabotropic NMDA receptors and brain-derived neurotropic factor has been shown to play a crucial role in ketamine's antidepressant effect. The American Psychiatric Association Council of Research Task Force on Novel Biomarkers and Treatments reviewed the data generated from seven placebo-controlled, double-blind (DB), randomized clinical studies on ketamine hydrochloride infusion therapy in the treatment of depression comprising 147 treated patients, which they state provide “compelling evidence that the antidepressant effects of ketamine infusion are both rapid and robust, albeit transient.” The treatment of concomitant pain and depression makes it even more alluring for the pain physician.
The unique pharmacokinetic and pharmacodynamic profile of ketamine lends itself for potential use outside of the hospital. Ketamine is a lipid-soluble molecule with a large volume of distribution (2.4 l/kg) that crosses the blood–brain barrier quickly and has a redistribution half-time of 10 min and a terminal elimination half-time of 2–3 h, with infusions; the context-sensitive half-time can increase substantially. It is metabolized by the cytochrome P450 enzyme CYP3A4 to norketamine, which is 33% as potent as its parent compound. The bioavailability of oral ketamine is approximately 10%–25% with an onset of 5–20 min which by first-pass metabolism produces significant norketamine adding to the potency of oral formulations., Intranasal ketamine is 25%–50% bioavailable (as it avoids the hepatic first-pass effect) with an onset of 5–10 min and duration of 45–120 min. This is in contrast to intravenous (IV) ketamine, which is 100% bioavailable and has an onset of 30 s. Topical ketamine has a bioavailability of <5% and an onset of <2 days, with unknown duration of action. Sufficed to say, ketamine can be administered in a wide variety of ways, maximizing the potential benefits of time to the patient, provider, and ease of administration.
Currently, ketamine is recommended in certain clinical pain syndromes, although dose range, patient selection, non-IV formulations, long-term sequelae, and efficacy still need to be elucidated. Few high-quality studies have addressed these concerns, with the majority of the studies not properly blinded and/or underpowered. Further, large multicenter DB studies are needed to fully understand the uses for ketamine in different pain syndromes.
A 2019 meta-analysis was recently published looking at the efficacy of IV ketamine infusions for chronic pain. Only placebo-controlled randomized controlled trials (RCTs) were included. Seven studies met the inclusion criteria, with two mixed, two neuropathic, and three nonneuropathic pain in focus. All studies assessed patients >48 h after infusion. Dosing regimens varied widely between studies. Infusion lengths ranged from 0.5 to 100 h (median = 1 h), infusion dose ranged 0.23–0.6 mg/kg (median = 0.35 mg/kg), and infusion days (intermittent or continuous) ranged 1–10 days (median = 1 day). The primary outcome measured was the lowest pain score on the Numerical Pain Rating Scale (NPRS) at ≥48 h after treatment cessation. They found a significant reduction in pain scores with ketamine over control groups (mean difference: −1.83 points; 95% confidence interval [CI]: −2.35 to − 1.31 points; P < 0.0001). When stratifying studies into high dose (>400 mg cumulative dose) and low dose (<400 mg cumulative dose), they found a dose–response trend to decreasing pain scores in the high-dose group. However, this difference was not significant (mean difference: −2.11 vs. −1.30 respectively, P = 0.213).
IV ketamine has been often used by pain physicians for treatment of challenging complex regional pain syndrome (CRPS)-related pain. In a study done by Sigtermans et al., sixty patients with CRPS were randomized to receive S(+)-ketamine infusions or placebo. A ketamine infusion was started at 1.2 μg/kg/min and was titrated to a maximum of 7.2 μg/kg/min for 5 days. Their primary outcome was pain scores measured on the NPRS, collected weekly from baseline to 12 weeks after intervention. They found a greatest reduction in pain scores in the ketamine group (ketamine 2.68 ± 0.51 and placebo 5.45 ± 0.48 at week 1, compared to baseline pain scores of 7.2 in the ketamine group and 6.87 in the placebo group). This effect lasted until week 11 and was lost at week 12. Of note, there were significantly more side effects in the ketamine group, such as nausea, vomiting, and psychomimetic effects.
Given the often wide variability in pain reduction seen in studies, certain patients may respond better than others. One study done by Bosma et al. attempted to elucidate which patients might respond to ketamine treatment. In this study, 30 patients with refractory neuropathic pain and 30 healthy controls underwent quantitative sensory testing and resting-state functional magnetic resonance imaging and then completed validated questionnaires. Patients then received outpatient IV ketamine (0.5–2 mg/kg/h; mean dose 1.1 mg/kg/h) for 6 h/day for 5 consecutive days. Pain was assessed 1 month later. At 1 month, almost half of the patients achieved ≥30% pain relief (referred to as responders). The study also found that patients with higher pretreatment dynamic connectivity and higher pretreatment levels of temporal summation of pain (TSP) had greater reduction in clinical pain from ketamine (median pretreatment TSP was 200 in responders compared to 44 in nonresponders).
A multicenter DB-RCT was conducted by Hardy et al. in 2012 in which subcutaneous ketamine or placebo was administered to 185 randomly assigned patients with chronic cancer pain. The dosage of ketamine was escalated over 5 days, from 100 mg, then 300 mg, and finally 500 mg. Dosages were only increased if the brief pain inventory (BPI) score did not improve by >2 or more points. The primary endpoint was defined as a reduction in BPI average pain score by ≥2 points from baseline in the absence of more than four breakthrough doses of analgesia over the previous 24 h. The response was 27% (25 of 92) in the placebo and 31% (29 of 93) in the intervention arm (P = 0.55). The number needed to harm was reported as 6 (95% CI: 4–13), as measured by actual withdrawal because of unacceptable toxicity. Further, there was no difference in mean pain levels at the study end (placebo, 3.49 [95% CI: 3.02–3.95] vs. ketamine, 3.11 [95% CI: 2.65–3.57]; P = 0.15). One of the critiques of the study is that titration was done fairly rapidly. A Cochrane review on the use of ketamine as an adjuvant for cancer-related pain recommends against rapid escalation, likely based on results of this trial.
Lauretti et al. performed an RCT in patients with chronic cancer-related pain in 1999. It was designed to assess the effects of oral ketamine or transdermal nitroglycerin on oral morphine consumption. Comparison groups included oral morphine alone and oral morphine with a nonsteroidal anti-inflammatory drug (NSAID). Sixty patients were enrolled and randomized into the four groups. Patients initially were given full access to increase their oral morphine dose up to 90 mg/day to keep their pain score <4 on the visual analog scale (VAS). When patients reached 90 mg/day, either ketamine (0.5 mg/kg q12 h), transdermal nitroglycerin, dipyrone (a NSAID), or additional morphine (20 mg/day) was added. Patients were again allowed to escalate their morphine doses freely, and differences in morphine consumption were recorded. Results showed a significant reduction in morphine use with ketamine compared to the control group on day 30 (exact numerical data not shown, ~75 mg/day vs. ~135 mg/day, respectively; P = 0.003).
However, a recent multicenter DB placebo-controlled RCT examining the effects of oral ketamine versus placebo on cancer-related neuropathic chronic pain failed to show its significance. Two hundred and fourteen patients were randomized, with half receiving oral ketamine on a dose escalation protocol and half receiving placebo. Patients were enrolled if they had cancer-related neuropathic pain >3/10 on the VAS despite an adequate trial with adjuvant medication (e.g., amytriptilene and gabapentin). Doses started at 40 mg/day and were titrated to the maximum dose possible without side effects (maximum 400 mg/day) over 2 weeks. Patients then received a stable dose of medication for 16 days and were subsequently withdrawn if no improvement was noted. Primary endpoint was defined as an improvement of ≥5 points on the SF McGill Pain questionnaire. No difference in duration of analgesic benefit was found between groups, as assessed by the adjusted (minimization factors) Cox proportional hazards model (ketamine to placebo hazard ratio: 0.95 [95% CI: 0.70–1.29]; P = 0.75). Interestingly, they noted eight serious adverse events in the ketamine group and ten in the placebo group.
The intranasal route of delivery for ketamine offers several advantages. It is a needle-free route of delivery that avoids the hepatic first-pass effect, resulting in a much higher bioavailability compared to oral, transdermal, or subcutaneous routes. The large surface area, high permeability, and extensive vascularity of the nasal mucosa result in rapid systemic absorption. Ketamine can be delivered intranasal by either a metered dose nasal spray prepared by a compounding pharmacy using ketamine powder or a mucosal atomizer device connected to a Luer locked syringe using commercially available ketamine.
A DB-RCT conducted by Carr et al. in 2004 which examined the effects of intranasal ketamine in chronic pain patients with breakthrough pain showed promising results. In this crossover study, 20 patients were randomized to receive either 10–50 mg of intranasal ketamine (patient-controlled dose in 10 mg aliquots) or placebo. The patients then crossed over to the alternate placebo group >47 h later. Patient suffered from a wide range of illnesses including cancer pain, back pain, fibromyalgia, and reflex sympathetic dystrophy. They reported that nine of 20 patients (45%) achieved a mean reduction in numeric pain intensity scale score of >40% compared to 1 of 20 patients (5%) following treatment with placebo (P = 0.0078).
In 2012, Huge et al. similarly administered intranasal ketamine to 16 patients with chronic neuropathic pain at dosages of either 0.2 or 0.4 mg/kg. They found that pain decreased most at 60 min after administration, with pain scores at 70% ± 10% of initial pain in the 0.2 mg/kg group and 61% ± 13% of initial pain in the 0.4 mg/kg group. Patients also underwent quantitative sensory testing before and after drug administration; however, no significant changes in somatosensory mechanical or thermal pain and detection thresholds were found.
One unique trial looking at the use of intranasal ketamine is the PRIME Trial. In this study, intranasal ketamine was compared to intranasal fentanyl for reducing moderate-to-severe pain in children aged 8–17 years with traumatic extremity injuries. The primary outcome assessed was reduction in VAS pain scores 30 min after intervention. This study found that ketamine was noninferior in its ability to reduce pain, though there was a slightly higher risk of adverse events.
Intranasal esketamine is also now gaining a great degree of publicity outside the realm of pain management following its Food and Drug Administration approval for the treatment of refractory depression. Despite ketamine's short half-life, approximately 3 h, it was found to have antidepressant effects as far as 8 weeks after intermittent administration. More data must be obtained before a true consensus on ketamine's use in this setting can be reached, but early studies provide a reason for hope and optimism for continued usage in this arena.
Topical formulations of ketamine can be prepared by compounding pharmacies. A topical 1% ketamine formulation along with 2% amitriptyline was studied for neuropathic pain in a DB-RCT by Lynch et al. In this trial with 92 patients, they were randomized to receive either placebo, 2% amitriptyline, 1% ketamine, or a combination of 2% amitriptyline and 1% ketamine three times a day for 3 weeks. It failed to show any significant pain relief with topical ketamine. However, a smaller open-label study of five patients with neuropathic pain, using higher strength of topical ketamine (10%), three times a day for 2 weeks, showed a significant reduction in pain scores on NPRS (14%–63% reduction) after 2 weeks.
Guidelines for Ketamine Infusion for Chronic Pain
In 2018, the American Society of Regional Anesthesiology and Pain Medicine (ASRA-PM), along with the American Academy of Pain Medicine and the American Society of Anesthesiologists, created guidelines to inform patient selection and standardization with IV ketamine infusion for chronic pain. These guidelines include the use of ketamine for short-term pain relief for CRPS (moderate evidence, Grade B), spinal cord injury (weak evidence, Grade C) with a multitude of other pain syndromes with weak or no evidence (Grade D). The only recommendation for intermediate- to long-term pain relief is with regard to the treatment of CRPS (moderate evidence, Grade B). In regard to the contraindications for its use, ASRA suggests to avoid in patients with poorly controlled cardiovascular disease, pregnancy, and active psychosis (all Grade B). It is also recommended to avoid in patients with severe hepatic disease (avoid), moderate hepatic disease (caution), and elevated intracranial and intraocular pressure and active substance abuse (Grade C). ASRA guidelines do not recommend routine testing for healthy individuals; an electrocardiogram may be indicated if there is concern for cardiovascular disease and pre- and post-infusion liver function tests if concerned for liver function (all Grade C). While the optimal dosing has not been fully elucidated, the ASRA recommends bolus dosing of up to 0.35 mg/kg, infusion of 0.5–2 mg/kg/h, and utilization of a higher dose of ≥80 mg (Grade C). The strongest recommendations come regarding the personnel administering the drug. They include having a supervising physician experienced with ketamine, who is trained in Advanced Cardiac Life Support as well as moderate sedation (Grade A). The administering clinician should be a physician, a registered nurse, or a physician assistant with formal training in moderate sedation (Grade A). Finally, in a setting where >1 mg/kg/h is being administered, resuscitative equipment and medications should be readily available (Grade A).
Ketamine may play a crucial role in treatment of certain intractable chronic pain conditions, such as CRPS, neuropathic pain, and cancer-related pain, as well as depression. The IV route is commonly utilized when delivering ketamine for chronic pain. Studies using topical, oral, and subcutaneous routes have yielded mixed results. The intranasal route might offer a needle-free, patient-friendly option for continued follow-up with ketamine; however, long-term safety data are needed. Poorly controlled cardiovascular disease, pregnancy, and active psychosis are the major contraindications to its use. Dose-related side effects such as its psychomimetic effects can limit its use. However, low-dose ketamine (<1 mg/kg) may provide analgesia and has gained a great deal of interest recently. Better designed clinical trials are needed to advance knowledge regarding analgesic use of low-dose ketamine, especially in the long term.
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