Ketamine

Ketamine

PEP Topic 
Refractory/Intractable Pain
Description 

Ketamine is a fast-acting, dissociative anesthetic that works by stopping external stimulation from being delivered to the brain from the nervous system. As such, it can give rise to a hallucinogenic state and distort perception. Ketamine is a schedule III drug in the United States. Ketamine is used as a general anesthetic and in pain management.

Benefits Balanced With Harm

Systematic Review/Meta-Analysis

Bell, R., Eccleston, C., & Kalso, E. (2003). Ketamine as an adjuvant to opioids for cancer pain. Cochrane Database of Systematic Reviews 2003, Issue 1. Art. No.: CD003351.

doi: 10.1002/14651858.CD003351
Print

Search Strategy:

DATABASES USED: MEDLINE (1996–2002); EMBASE (1980–2002); CANCERLIT (1966–2002); Cochrane Controlled Trials Register and Database of Systematic Reviews (Cochrane Library, Issue 1, 2002); Specialized Register of the Cochrane Pain, Palliative and Supportive Care Group (2001); PARDLARS (in-house database of Pfizer UK, February 2002); hand-searching reference lists

Literature Evaluated:

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Two RCTs met inclusion criteria. Two other RCTs appeared to meet the criteria but were considered methodologically flawed. Thirty-two case reports or open-label uncontrolled trials could not be included.

Sample Characteristics:

FINAL NUMBER STUDIES INCLUDED = 2

TOTAL PATIENTS INCLUDED IN REVIEW: 30

KEY SAMPLE CHARACTERISTICS: Seventeen men and 13 women aged 21–69 years. Cancers included stomach, cervix, liver, lung, colon, pancreas, bladder, rectum, histiocytoma, and uterus. The first study included 20 patients whose pain had been treated successfully with opioids. The second study included 10 patients whose pain had been unrelieved by their dose of morphine. In the second study, pain was defined as “neuropathic,” and the patients had a Karnofsky score of 50 or more.

Results:

Pain scores were reduced in those patients receiving ketamine. Four patients experienced hallucinations (most common adverse effect associated with ketamine). Two of those four patients also experienced a sensation of insobriety. All of these effects were relieved by diazepam.

The following treatments were evaluated.

  • Ketamine 0.25 mg/kg adjuvant to morphine given IV
  • Ketamine 0.5 mg/kg adjuvant to morphine given  IV
  • Ketamine 1 mg/kg co-administered intrathecally with morphine (reducing the morphine dose)

The primary outcome measure was patient-reported pain intensity and pain relief, using validated measures on movement and at rest (e.g., visual analog scale and verbal rating scale). Secondary outcomes included total opioid consumption, rescue medication, adverse events, study withdrawals, and dropouts.

Conclusions:

The objective of the systematic review was to assess the effectiveness of ketamine as an adjuvant therapy in treating cancer pain. Because of the small number of RCTs, small sample sizes, and lack of other acceptable research, evidence is insufficient to make the use of ketamine as an adjuvant to opioids a recommendation for practice.

Nursing Implications:

Suggested for research are crossover designs, larger patient groups, comparisons with other opioids, comparisons of routes of administration, and clearly defined outcomes. Research into ketamine’s role as an NMDA antagonist also would be welcomed.

Bell, R.F., Eccleston, C., & Kalso, E.A. (2012). Ketamine as an adjuvant to opioids for cancer pain. Cochrane Database of Systematic Reviews 2012, Issue 11. Art. No.: CD003351.

doi: 10.1002/14651858.CD003351.pub2
Print

Purpose:

To determine the efficacy and adverse effects of ketamine as an adjuvant to opioids in the treatment of cancer pain

Search Strategy:

Databases searched were CENTRAL, MEDLINE, EMBASE, PubMed, and the Pfizer Product Information Database.

Studies were included in the review if they

  • Were randomized clinical trials (RCTs).
  • Involved adult patients with cancer pain being treated with opioids.
  • Studied patients receiving ketamine at any dose or route for cancer pain or a placebo or active control.

Studies were excluded if they had fewer than 10 participants.

Literature Evaluated:

A total of 120 references were retrieved. Studies were selected based on criteria, assessed independently, reviewed by two reviewers, and chosen for inclusion by three independent reviewers.

Sample Characteristics:

  • The final number of studies included was two.
  • The total number of patients included in the review across studies was 30.
  • Of these patients, 20 were hospitalized with cancer pain unrelieved effectively with opioids who received two different doses of IV ketamine (0.25 mg or 0.5 mg) and 10 were patients with neuropathic pain unrelieved by opioids.

Phase of Care and Clinical Applications:

  • Patients were at the end-of-life phase of care.
  • This study has clinical applicability for palliative care.

Results:

  • For IV ketamine, the 0.5 mg dose demonstrated a significant reduction in pain intensity and the relief was sustained throughout the three-hour measurement period.
  • For intrathecal ketamine, pain was controlled on reduced doses of intrathecal opioids or on ketamine alone.

Conclusions:

Current evidence is insufficient to assess the benefits and harms of ketamine as an adjuvant to opioids in the relief of cancer pain because of the small number of trials with low sample sizes.

Limitations:

  • The sample size was small, with only 30 patients.
  • Few RCTs exist on this topic.
  • Doses and routes of administration of ketamine were different, measurement of pain was variable, the type of pain was variable (one study was of neuropathic pain but not the other), and the time for measurement was not consistent.

Nursing Implications:

Although studies suggest that ketamine may be a helpful adjuvant therapy to improve pain and decrease opioid requirements in patients with cancer, more studies are needed with larger sample sizes and control groups. Evidence is lacking to recommend ketamine in practice.

Research Evidence Summaries

Hardy, J., Quinn, S., Fazekas, B., Plummer, J., Eckermann, S., Agar, M., … Currow, D.C. (2012). Randomized, double-blind, placebo-controlled study to assess the efficacy and toxicity of subcutaneous ketamine in the management of cancer pain. Journal of Clinical Oncology, 30, 3611–3617.

doi: 10.1200/JCO.2012.42.1081
Print

Study Purpose:

To determine whether ketamine, delivered subcutaneously with dose titration over five days, has greater clinical benefit than placebo when used in conjunction with opioids and standard adjuvant therapy in the management of cancer pain

Intervention Characteristics/Basic Study Process:

  • Patients received either a continuous subcutaneous infusion of ketamine on a five-day, escalating-dose schedule (100 mg, 300 mg, and 500 mg over 24 hours) or placebo (normal saline) given over five days. 
  • Patients were assessed every 24 hours for pain (least, average or best)  using the Brief Pain Inventory (BPI). No dose change occurred if 80% of ketamine was delivered, pain improvement was greater than 2, and no more than four breakthrough pain doses were needed.
  • Dose reductions occurred if toxicity was unacceptable. The drug was discontinued at 500 mg if no response to pain occurred or toxicity became intolerable.

Sample Characteristics:

  • The study reported on 149 patients with a mean age of 63.
  • The sample was 55% male and 45% female.
  • Patients had refractory pain secondary to cancer or its treatment.
  • For 48 hours prior to beginning the study, participants could have no change in baseline opioid dosing. 
  • Patients were excluded if they had received ketamine within the past six months, had radiotherapy to a site of pain within two weeks, or received any other procedure that may affect pain.

Setting:

This was a multisite, inpatient study conducted in Australia.

Phase of Care and Clinical Applications:

  • Patients were in the late effects and survivorship phase of care.
  • This study has clinical applicability for palliative care.

Study Design:

This was a randomized, double-blinded, placebo-control study.

Measurement Instruments/Methods:

  • The Common Terminology Criteria for Adverse Events v 3.0, Clinician-Administered Dissociative States Scale, and BPI were used.
  • A positive response was defined as a clinically relevant improvement in pain.

Results:

  • Findings showed no significant differences between study groups. Pain declined somewhat over time in both groups. The decline in worst pain ratings was lower in the ketamine group (p = 0.034). No differences were found between groups in use of rescue medication.
  • More patients withdrew from the ketamine arm. The incidence of adverse events was higher with ketamine.
  • The most common events were light headedness, hypoxia, and somnolence. Psychotoxicity significantly increased each day, and, by day 3, the odds of psychotoxicity development were significantly higher in the ketamine group (OR = 2.53; 95% CI [1.11, 5.78]; p = 0.027).

Conclusions:

Ketamine was only associated with improvement in worse pain compared to placebo, and it was associated with more adverse events and psychotoxicity.

Limitations:

  • A risk of bias exists because of the sample characteristics.
  • The findings are not generalizable.
  • Entry inclusion criteria included an average pain score of 3 or more on BPI. This may not reflect clinically acceptable pain of 3 or 4. 
  • Concerns exist regarding the aggressive dosing and short duration of the study. The short duration of the study over five days with rapid escalation of ketamine may have been overly aggressive. A question exists around whether more careful titration of ketamine may have altered results.

Nursing Implications:

Ketamine as an adjunct to opioids to manage chronic refractory cancer pain only appeared to affect worst pain rating and may cause adverse effects and increase psychotoxicity. Incidence of adverse events with ketamine infusion adjunctively with opioids in the management of refractory pain should be reevaluated when considering the patient population of advanced cancer.

Jackson, K., Ashby, M., Howell, D., Petersen, J., Brumley, D., Good, P., … Woodruff, R. (2010). The effectiveness and adverse effects profile of "burst" ketamine in refractory cancer pain: The VCOG PM 1-00 study. Journal of Palliative Care, 26(3), 176-183.

Print

Study Purpose:

To assess the efficacy and adverse effects of a ketamine burst protocol for pain relief in patients with refractory pain

Intervention Characteristics/Basic Study Process:

Patients received IV ketamine at three dose levels (100, 300, and 500 mg per 24 hours) over 3–5 days in inpatient palliative care settings. All other medications remained, and benzodiazepines or haloperidol could be used to minimize adverse psychotomimetic events. Maintenance doses of 24 opioids and breakthrough pain opioid dosing could be reduced as appropriate for pain control. Data were collected on pain scores and total opioid intake during ketamine infusions and for 48 hours post infusion.

Sample Characteristics:

  • The sample consisted of 44 patients.
  • The median age was 61 years, with a range of 35–82 years.
  • The sample was 52% female and 48% male.
  • The majority of primary malignancies were lung, breast, colorectal, head and neck, mesothelioma, and multiple myeloma.
  • Patients had various types of pain, including neuropathic (64%), pain from bony metastases (25%), and somatic pain (32%).
  • All patients had pain scores of 4 or more at baseline, using a verbal rating scale.
  • Pretreatment morphine-dose equivalents for opioid intake ranged from 3–1,050 mg per 24 hours.

Setting:

This was a multisite study conducted in an inpatient setting in Australia.

Study Design:

This was an open-label, prospective study.

Measurement Instruments/Methods:

Patients were assessed based on the European Cooperative Oncology Group (ECOG) performance status, National Cancer Institute (NCI) Common Toxicity Criteria, and a pain verbal rating scale (which was not described).

Results:

  • In all, 77% of patients required 300 mg or more of ketamine and 41% required 500 mg per 24 hours. Half of the participants were classified as responders to the ketamine.
  • The longest documented response was 3 months in one patient; 11 patients continued with defined response for 2 weeks.
  • More than half (61%) of patients experienced low-grade adverse effects. All grade 3 and 4 side effects occurred in patients who needed at least  300 mg per 24 hours of ketamine.
  • Injection site toxicity was the most frequent grade 3 toxicity, and the most frequent grade 4 toxicity was hallucinations. No responding patient required withdrawal because of neurological adverse events.

Conclusions:

Findings suggest that use of a ketamine burst infusion may be helpful for pain relief in some patients with cancer-related refractory pain.

Limitations:

  • The sample size was small, with fewer than 100 patients.
  • No comparison or control group was included.
  • Opioid intake and episodes of breakthrough pain were not reported, although these were stated as outcomes of interest in the study.
  • Refractory pain was defined as at least 4 on the rating scale, but duration of pain was not described in the population.
  • Use of adjuvant pain medications was not described; therefore, subgroup analyis could not be done based on other medication intake.
  • Statistical analysis of findings was not included.

Nursing Implications:

In patients with pain that is not effectively controlled by other means, approaches such as ketamine infusions may have some benefit. More research in ketamine use is warranted. Although some patients responded and had a duration of effect as long as three months, 50% of patients did not respond as defined. Use of this approach requires hospitalization with continuous infusion and monitoring.

Salas, S., Frasca, M., Planchet-Barraud, B., Burucoa, B., Pascal, M., Lapiana, J.M., … Baumstarck, K. (2012). Ketamine analgesic effect by continuous intravenous infusion in refractory cancer pain: Considerations about the clinical research in palliative care. Journal of Palliative Medicine, 15(3), 287–293.

doi: 10.1089/jpm.2011.0353
Print

Study Purpose:

To assess the efficacy of continuous IV infusion of ketamine in patients suffering from opiate-refractory cancer pain admitted to palliative care units

Intervention Characteristics/Basic Study Process:

Patients were computer randomized to either IV morphine plus ketamine or morphine plus placebo. Morphine could be titrated by 50% once daily. Evaluations were performed at baseline, 2 hours, 24 hours, and 48 hours after initiation of infusion. Ketamine was given at continuous infusion of 0.5mg/kg per day and increased to 1mg/kg per day if pain score did not improve after 24 hours.

Sample Characteristics:

  • The sample consisted of 20 patients (11 experimental and 9 control) with a mean age of 60.3 years.
  • The sample was 70% male and 30% female.
  • Key disease characteristics were  not included.

Setting:

This was a multisite study conducted in France.

Phase of Care and Clinical Applications:

  • Patients were in the end-of-life phase of care.
  • The study has clinical applicability to end of life and palliative care.

Study Design:

This was a randomized, double blind, placebo-controlled study.

Measurement Instruments/Methods:

  • Pain was rated using a Numeric Pain Intensity Scale from 0–10.
  • The Edmonton Symptom Assessment Scale and Patient Treatment Satisfaction Scale were used.
  • Daily morphine dose was recorded.
  • The Epworth Sleepiness Scale (ESS) was used to record daytime sleepiness.

Results:

Pain did not significantly differ between the two groups. No significant differences were found in morphine changes, ESS scores, or satisfaction scores between the two groups.

Conclusions:

The combination of morphine and ketamine did not improve pain or decrease opioid requirements.

Limitations:

  • The sample size was small, with fewer than 30 patients.
  • Ketamine doses were not titrated, and only one dose was trialed. A dose finding trial is needed.

Nursing Implications:

Although ketamine did not improve pain scores in patients with opiate refractory pain, further studies are needed because of study limitations.


Menu