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Subanesthetic ketamine: an essential adjuvant for intractable cancer pain

      To the Editor:
      We read the review article on the use of ketamine as an adjuvant to opioids for cancer pain
      • Bell R.F
      • Eccleston C
      • Kalso E
      Ketamine as adjuvant to opioids for cancer pain. A qualitative systematic review.
      with great interest. Ketamine is considered an adjuvant analgesic and is on the WHO Essential Drugs List for patients who no longer respond to high doses of morphine or who have predictable breakthrough pains.
      • Colleau S.M
      • et al.
      The essential adjuvant analgesics for neuropathic pain.
      Its beneficial effect results predominantly from the blockade of N-methyl-D-aspartate receptor, which is involved in central summation and sensitization, as well as in opioid tolerance and opioid-induced pain sensitivity.
      • Mao J
      • Price D.D
      • Mayer D.J
      Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions.
      • Fisher K
      • Coderre T.J
      • Hagen N.A
      Targeting the N-methyl-D-aspartate receptor for chronic pain management: preclinical animal studies, recent clinical experience and future research directions.
      • Jensen T.S
      • Baron R
      Translation of symptoms and signs into mechanisms in neuropathic pain.
      • Mao J
      Opioid-induced abnormal pain sensitivity: implication in clinical opioid therapy.
      • Mercadante S
      Burst ketamine to reverse opioid tolerance in cancer pain.
      However, the mechanism of action is thought to be more complex, involving pro-inflammatory cytokine synthesis inhibition and an influence on monoamines.
      Ketamine, supplemented by midazolam, has been used in the Poznan Palliative Care Department as an intravenous agent to provide analgesia and sedation during hygienic/nursing painful procedures and as an adjuvant to morphine since 1989. We reported the early observations of 12 cases at the 6th Conference of St. Christopher's Hospice in London in 1991.

      Luczak J. The use of ketamine in the palliative care setting for the treatment of terminal cancer pain. The Sixth International Conference of St. Christopher's Hospice. London, May 1991.

      Since then, we have used ketamine as a co-analgesic in a further 57 patients (4–8 from about 1,000 referrals a year).
      • Luczak J
      • Dickenson A.H
      • Kotlińska-Lemieszek A
      The role of ketamine, an NMDA receptor antagonist, in the management of pain.

      Kotlińska-Lemieszek A, Luczak J, Baczyk E, et al. Subanesthetic ketamine—an essential adjuvant for intractable cancer pain. 4th Congress of EFIC, Prague September 2003, Abstract No 468.

      The indications were: 1) moderate to severe pain (especially of neuropathic origin) despite opioid dose escalation and opioid rotation, and 2) high incidence of breakthrough pain requiring intravenous rescue doses of a strong opioid and midazolam. Of the group of 69 patients (34 female and 35 male aged 9 to 78 years old [mean 48]), 23 patients (33%) had cancer involving organs located in the pelvis (mainly cervix and rectum), 13 (about 20%) had lung cancer, 6 had head and neck cancer, and 4 had breast cancer. Plexopathies were the cause of intractable pain in 38 patients (55%), spinal cord compression in 16 (23%), nerve root involvement in 7, and CNS tumors in 3. Tenesmus was the cause of unrelieved pain of nociceptive origin in 8 patients, and bone pain exacerbated on movement in 7; 5 patients had other types of nociceptive pain. In 15 cases, two origins of pain coexisted. In the majority of patients, ketamine (racemate preparation for injection—Ketanest, Parke-Davis, Calypsol, Richter Gedeon) was used subcutaneously or orally, and subsequently subcutaneously (when difficulty swallowing occurred). Intravenous infusions were commenced when subcutaneous treatment failed or there were very severe dynamic breakthrough pain episodes. Epidural treatment was implemented in two patients. Ketamine for subcutaneous use was mixed in one syringe with morphine and given as an injection every 4 hours or as a continuous infusion. Ketamine for oral use was diluted with water or juice and given every 4 hours, with the night dose increased by 50%. The doses of ketamine were very variable and ranged from 13 mg/day (starting dose in one patient) to over 1,400 mg/day. In the majority of patients, the dose did not exceed 400 mg/day (median 195 mg/day). The oral morphine equivalent doses in these patients equaled 60–11,500 mg/day. Reduction of morphine dose after ketamine was started was possible in 17% of patients. The duration of treatment ranged from 4–195 days. In this selected cancer population, in which pharmacotherapy including morphine and adjuvants acting by various mechanisms, as well as spinal analgesia in some patients, had not been effective, complete pain relief (judged as a numeric scale below 3 and fewer than 2 episodes of breakthrough pain a day) was observed in 62%; partial relief occurred in 23%, and the therapy failed in 15%. In order to prevent threatening dreams, confusion and hallucinations, diazepam, midazolam (starting with 5 mg/24 hours), and/or haloperidol (starting with 2 mg/24 hours) was used. Despite this preventive treatment, threatening dreams and confusion occurred with a high incidence of 14.5% and 22%, respectively. Drowsiness developed in 56.5%. Respiratory depression occurred in 1 patient and was reversed by 0.4 mg naloxone IV. Ketamine was continued in this patient till her death 3 weeks later, but the dose of this agent, as well as morphine, was escalated very cautiously (by 10–20%).

      1. Case 1

      A 47-year-old woman with carcinoma of the cervix suffered neuropathic pain (burning and spontaneous stabbing). She was treated with increasing doses of morphine and adjuvant drugs for over 6 months; later fentanyl TTS was added. During the next 3 months, the dose of oral morphine increased to 1,000 mg/day and fentanyl was increased to 200 μg/hr. Despite this treatment, she was suffering pain that was scored as 8–9/10 on a numeric scale. On admission to the inpatient unit, her oral morphine was changed to subcutaneous morphine at 820 mg/day and 70 mg of ketamine supplemented with 10 mg of midazolam. During the next 5 days, the doses of morphine and ketamine were titrated against effect to 1,200 mg/day and 105 mg/day, respectively. She became pain-free, but very drowsy. After the doses of both drugs had been reduced by about 30%, the analgesic effect was maintained and the drowsiness decreased. She died peacefully 50 days later.

      2. Case 2

      A 34-year-old man with sarcoma of the femur and secondaries to the spine and the lungs suffered pain due to the fracture of L1 and spinal cord compression. He was started on subcutaneous morphine (up to 240 mg/day), amitriptyline, diclofenac, and clonazepam with no relief (numeric scale 8–9/10). Subsequently, he was given ketamine. His pain resolved in a few hours after the first dose. Until his death 4 months later, the doses of both drugs had to be titrated up to 1,030 mg/day of morphine and 255 mg/day of ketamine. Additionally, he required extra doses for breakthrough pain 2–5 times a day and for daily hygienic procedures. Two days before his death, his pain exacerbated and he received multiple rescue doses.

      3. Comment

      Ketamine was synthesized and introduced into clinical practice over 38 years ago and is an anesthetic of choice for poor-risk patients due to its cardiovascular stimulating effect and negligible respiratory depressant properties. For those reasons, this drug has been used in everyday practice in our unit in patients with ulcerations or severe pain on movement (fracture of the vertebra) before painful hygienic procedures or dressing changes, and during conveyance to the hospice. Intravenous ketamine in fractionated doses, starting with 5–10 mg, provides analgesia and sedation in up to 15 minutes. A dose of 20–40 mg, preceded by a 1–2 mg bolus injection of midazolam, is sufficient in the majority of patients.
      • Luczak J
      • Dickenson A.H
      • Kotlińska-Lemieszek A
      The role of ketamine, an NMDA receptor antagonist, in the management of pain.
      Based on our experience, we offer the following recommendations. When ketamine is indicated:
      • 1.
        Start with a test dose of ketamine, for example, 2.5–5 mg IV or SC, 20 mg PO. Assess the efficacy and side effects. Add midazolam 1 mg IV if vivid/threatening dreams occur.
      • 2.
        Commence ketamine on a regular basis, starting with 0.6–0.8 mg/kg/day orally or subcutaneously.
      • 3.
        Order midazolam concomitantly.
      • 4.
        Titrate the dose of ketamine, increasing it by 25–30%, until pain is relieved or side effects limit further dose escalation.
      • 5.
        Reduce morphine dose if possible (in the majority of patients, however, there is the necessity to titrate up the dose).
      • 6.
        Give extra doses for breakthrough pain (1/10–1/6 of the oral or subcutaneous daily dose or 5–10 mg IV), to cover dressing changes, etc.
      • 7.
        Adjust the dose of midazolam/haloperidol if side effects occur.
      During the period when ketamine is introduced, the patient should be supervised in an inpatient unit. Discharge to home care is possible after pain control has been achieved.
      Ketamine in subanesthetic doses has proved to be a very effective adjuvant analgesic when other treatments fail to relieve pain in cancer patients, irrespective of the cause of the phenomenon termed ‘opioid poorly responsive pain’ (neuropathic pain, hyperalgesia induced by opioid treatment or opioid tolerance).

      Acknowledgements

      The authors wish to thank the Editor for publishing this letter, which allows is to share our 15 years' experience with the use of ketamine in the palliative care setting. We have found that this drug has unique effectiveness and a clear role in patients who are facing death and suffering agonizing unrelieved pain.

      References

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        Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions.
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        • Hagen N.A
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        Translation of symptoms and signs into mechanisms in neuropathic pain.
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        Opioid-induced abnormal pain sensitivity: implication in clinical opioid therapy.
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        Burst ketamine to reverse opioid tolerance in cancer pain.
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