Long-term intrathecal S(+)-ketamine in a patient with cancer-related neuropathic pain

J. Benrath*, G. Scharbert, B. Gustorff, H.-A. Adams1 and H. G. Kress

Department of Anaesthesiology and Intensive Care B, Medical University Vienna, Vienna, Austria. 1 Department of Anaesthesia and Intensive Care, Medical University Hanover, Hanover, Germany

* Corresponding author. E-mail: justus.benrath{at}meduniwien.ac.at

Accepted for publication April 25, 2005.


    Abstract
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 Abstract
 Introduction
 Case report
 Discussion
 References
 
Neuropathic pain sometimes needs invasive pain therapy. We present the case of a patient with cancer-related neuropathic pain untreatable with conventional pain therapy after tumour-embolization. The patient was treated successfully with intrathecal (i.t.) administration of S(+)-ketamine, in addition to morphine. Plasma concentrations of S(+)-ketamine were measured regularly throughout the treatment. Continuous i.t. administration of S(+)-ketamine over a period of 3 months demonstrated low plasma levels and no unwanted side-effects.

Keywords: anaesthetic administration, intrathecal ; anaesthetic administration, long-term ; anaesthetics i.v., S(+)-ketamine ; pain, cancer-related ; pain, neuropathic


    Introduction
 Top
 Abstract
 Introduction
 Case report
 Discussion
 References
 
The involvement of spinal N-methyl-D-aspartate (NMDA) receptors in the generation and maintenance of chronic pain states in animal models is well established.1 The NMDA-receptor antagonist ketamine is used in patients who suffer from cancer pain2 or neuropathic pain.3 4 However, the use of ketamine in chronic pain is limited, as a result of low enteral absorption and unpleasant side-effects from i.v. continuous infusion. An interesting but rarely used alternative is the intrathecal (i.t.) administration of ketamine. We have recently reported the successful treatment of non-malignant pain with S(+)-ketamine i.t. for 3 weeks.5 In addition to our experience, two case reports of successful 7-day6 and 3-week7 i.t. administration of racemic ketamine in patients with tumour pain have been published.

We present the successful treatment of a patient with severe cancer-related neuropathic pain by continuous i.t. administration of S(+)-ketamine over 92 days.


    Case report
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 Abstract
 Introduction
 Case report
 Discussion
 References
 
The patient was a 58-yr-old obese man (185 cm, 120 kg) with a history of urethral carcinoma diagnosed 18 months before he presented to our pain clinic. Tumour infiltrations were confirmed by radiography and MRI (Fig. 1) in the right gluteus muscles, the sacrum and right ileal bone leading to a pathological fracture. Additionally, a metastasis at the fifth lumbar vertebral body with intraspinal tumour growth had occurred, without any signs of paralysis. He had already received radio-chemotherapy and further oncological treatment included tumour embolization via the right internal iliac artery. Immediately after embolization, the patient suffered from continuous intolerable pain with a rating of 10 on the visual analogue scale (VAS; 0=no pain, 10=worst possible pain), despite treatment with mefenamic acid 2 g day–1, carbamazepine 200 mg day–1, amitryptiline 25 mg day–1, transdermal fentanyl 200 µg h–1, and morphine 5 mg h–1 i.v. with optional 10 mg bolus doses, up to 4 per hour, from a patient-controlled analgesia system.



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Fig 1 T1-weighted MRI-picture at the level of the fifth lumbar vertebral body shows the tumour invading the right ileum, gluteus, and spinal muscles (white frame). Additionally, a metastasis in the fifth lumbar vertebral body with intraspinal tumour growth is seen (white frame).

 
An i.t. catheter was placed at L3/4 and treatment started with morphine 3.6 mg day–1 and bupivacaine 30 mg day–1 via an external pump. Over the following 5 days the patient's pain was refractory to increased doses of morphine up to 120 mg day–1 and clonidine 360 µg day–1. The patient had continuous burning pain (VAS 5) and intense episodes of lancinating pain (VAS 10) in the right leg (Table 1). We added S(+)-ketamine i.t. (Ketanest® Pfizer, Vienna, Austria) initially at 7.5 mg day–1 and increased to 50 mg day–1 on day 10. This led to an immediate and dramatic reduction in pain and the i.t. morphine could be reduced (Table 2). The lancinating pain was completely abolished within hours but low-level continuous burning pain (VAS 2–4) remained. Because of the pathological fracture, standing and walking still produced severe pain (VAS 10). The treatment continued successfully, without any side-effects, and allowed reduction of morphine and clonidine doses. A pump for i.t. infusion (synchro Med EL; Medtronic, Minneapolis) was implanted 7 days after the start of S(+)-ketamine. The patient was able to go home, and returned once a week to our outpatient clinic for blood sampling and filling of the pump reservoir.


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Table 1 Pain escalation before i.t. S(+)-ketamine. I.T. administration of morphine, clonidine and intermittent bupivacaine and drugs given orally (dose per day) and resulting pain intensity expressed on a VAS (VAS; 0=no pain, 10=worst possible pain)

 

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Table 2 Drug requirements following introduction of i.t. S(+)-ketamine. I.T. administration of S(+)-ketamine, morphine, clonidine, and intermittent bupivacaine and oral drugs (dose per day) and resulting pain intensity expressed on VAS (VAS; 0=no pain, 10=worst possible pain)

 
Pain relief was satisfactory over 10 weeks (VAS 0–4 on rest) with a constant i.t. dose of S(+)-ketamine 22.5 mg day–1, morphine 36 mg day–1 and clonidine 300 µg day–1. Thereafter, the i.t. S(+)-ketamine was increased to 30 mg day–1 to control a moderate increase in pain but morphine and clonidine doses were decreased (Table 2). No psychomimetic side-effects, such as sedation, dysphoria, or hallucinations, were noted at any time. The patient died 92 days after the start of the i.t. S(+)-ketamine treatment with moderate pain levels at rest. Plasma concentrations of S(+)-ketamine were determined by high pressure liquid chromatography with UV-detection (HPLC-UV) throughout the treatment (Table 3).8


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Table 3 Plasma concentration of S(+)-ketamine during i.t. administration of S(+)-ketamine

 

    Discussion
 Top
 Abstract
 Introduction
 Case report
 Discussion
 References
 
The patient had severe neuropathic pain refractory to standard pain therapy with high dose anti-neuropathic medication orally and i.t. morphine. He was treated successfully with i.t. S(+)-ketamine. Direct anti-neuropathic pain effects of ketamine are attributed to its NMDA-receptor antagonism, shown in animal studies,9 case reports,10 and clinical trials.11 12 Additionally, ketamine may have enhanced the spinal action of morphine.13 14

The patient's pain may have been exacerbated by the development of tolerance to morphine. The dosage of morphine i.t. was increased up to 120 mg day–1 and clonidine 360 µg day–1 was added but, despite this, neuropathic pain remained. Based on our experience of a patient with opioid tolerance in non-tumour pain we decided to add S(+)-ketamine i.t. to the morphine.5 Continuous i.t. administration provided good analgesia and allowed the progressive reduction of the daily morphine dose without signs of opioid withdrawal.

I.T. ketamine was described 20 yr ago15 but there are only a few reports of continuous i.t. administration. An advantage of the i.t. route is the lower drug dose, which potentially reduces side-effects. In our case, a dose of 22.5 mg day–1 was sufficient to treat the neuropathic element of the pain. Initially, doses of up to 50 mg day–1 S(+)-ketamine were used, which is similar to that in our recent study where doses up to 47.2 mg day–1 were used.5 A dose of 67.2 mg day–1 has been shown to cause unwanted side-effects, such as acute psychotic alterations, 7 days after the start of treatment.7 In our case, there were no signs of side-effects, such as arterial hypertension, psychomimetic alterations, or neurological dysfunction, at any time.

There is no pharmacokinetic information on continuous i.t. administration S(+)-ketamine available. In our case, the ketamine dosage remained constant over 11 weeks. No loss of efficacy and no accumulation in the plasma were found (Table 3). The higher concentration seen 2 weeks after the start may be explained by the relatively high doses on days 9–12 (Tables 2 and 3).

Recent studies and reviews have raised concerns about the neurotoxicity of ketamine suggest that the neurological lesions reported may be caused by the preservatives benzethonium chloride or chlorobutanol used in racemic ketamine solutions.6 16 17 S(+)-Ketamine is a preservative-free formulation and therefore seems suitable for i.t. administration. However, there are no histological studies of the effect of S(+)-ketamine given intrathecally.

Ketamine can be given by a number of other routes including s.c., epidural, i.m., oral, nasal, rectal, and transdermally.18 These are all possible routes for ketamine administration and the treatment of neuropathic pain using i.v. and s.c. routes has been described.18 We used an implanted catheter to avoid the use of an additional long-term device.

In summary, the continuous i.t. administration of the S(+)-ketamine enantiomer proved to be effective in a patient with severe neuropathic cancer pain refractory to conventional pain therapy. The absence of side effects over 3 months together with low plasma concentration favours the i.t. administration of S(+)-ketamine as an option in severe neuropathic cancer-related pain. However, this route of administration should be considered as a last resort, because of the potential for neurotoxicity.


    References
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 Abstract
 Introduction
 Case report
 Discussion
 References
 
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