Trial Information

Oral Ketamine as an Adjuvant to Opioids for Pain Treatment in Cancer Patients

It is estimated that 10%-15% of patients with cancer-related pain do not achieve acceptable
levels of pain relief even when oral or parenteral opioids are skillfully combined with
conventional adjuvant analgesics and intractable pain occurs in up to 2% of advanced cancer
patients. Painful conditions arising from tumor-nerve structure involvement, neuropathic
pain, skin lesions, iatrogenic (chemo-and radiotherapy lesion), or ischemic pain are those
most likely to require more aggressive treatment, such as the use of unconventional agents
or interventional management approaches.

Despite considerable progress in the technologies of cancer-related pain management and an
increased broadening array of medications, many patients fail to achieve adequate pain
relief. In others, the availability of these treatments may be limited by such factors as
side effects, or lack of or pain-management expertise. Furthermore, the development of
opioid tolerance and the high incidence of side effects with escalating dose of opioid dose
may contribute to treatment failure.

The need to develop new pharmacologic approaches for refractory pain remains of critical
importance. The most potent class of analgesics available for general use remains the
opioids.

Several lines of investigation have focused on the neuro-physiological as well as
neuro-chemical mechanisms that may underlay opioid resistant pain, such as opioid induced
hyperalgesia and opioid tolerance cause certain types of pain to be relatively resistant to
the opioids or that may underlie the tolerance that can develop to their beneficial effects.
Particular attention has been paid to the role played by glutamate neurotransmission in
promoting and maintaining chronic pain states.

Glutamate is the primary excitatory neurotransmitter of the central nervous system and is
normally released by pain-signaling afferent neurons as they synapse on central pain
pathways in the spinal cord. The persistent release of glutamate, due to peripheral injury
or inflammation, leads to the activation of N-methyl-D-aspartate (NMDA) receptors. This
process of activation has been shown to play a crucial role in mediating the phenomenon of
"wind up" pain, a state in which spinal neurons become hyper-responsive to repetitive
painful stimulation.

The clinically observed phenomena of allodynia (pain due to a stimulus that does not
normally provoke pain) and hyperalgesia (an increased response to a stimulus that is
normally painful), which are the hallmarks of neuropathic pain, are expressions of "wind up"
pain. Recent investigations indicate that this process can be prevented or mitigated by
agents that block the effects of glutamate at the NMDA receptor. Other investigations have
revealed that NMDA receptor antagonists can be useful in potentiating the analgesic efficacy
of several classes of medication, including opioids, nonsteroidal anti-inflammatory drugs
(NSAIDs), and local anesthetics. In addition, NMDA receptor antagonists may play an
important role in mediating the development of opioid tolerance or in treating the
perplexing syndrome of opiate-induced hyperalgesia.

Of the small number of NMDA receptor antagonists currently available for clinical use, most,
unfortunately, either have a narrow therapeutic window or require parenteral administration.
Dextromethorphan, best known for its use as an antitussive agent, is dosed orally and shows
activity as a noncompetitive NMDA antagonist. Multiple trials, however, generally have not
shown dextromethorphan to be effective in treating neuropathic pain.

Ketamine, a phencyclidine (PCP) derivative analog, has been used for more than 40 years to
produce "dissociative" anesthesia.

Early experience with ketamine revealed that it also produced analgesia that sometimes well
outlasted its anesthetic effects. Although the mechanisms of ketamine's analgesic effects
remain the subject of debate, and are likely multiple, antagonism at the NMDA-receptor site
appears to be central to both its anesthetic and analgesic effects.

Ketamine's utility as an anesthetic has been hampered by troublesome psychomimetic effects,
which for many years have also limited its application as an analgesic. Recent
investigations have shown, however, that analgesia can be produced with sub-hypnotic
sub-anesthetic doses of intravenous ketamine (ie,10%-20% of those used for anesthesia) with
a far lower frequency of psychomimetic reactions. These side effects are dose dependent and
can be minimized by starting ketamine at low doses, titrating slowly, and concurrently
starting a benzodiazepine or haloperidol.

Over the years a variety of nociceptive (somatic and visceral) and neuropathic pain states
have been treated with subanesthetic doses of ketamine. Early studies demonstrated its
utility in treating the pain associated with wound dressings in burn patients, as a
treatment for pain following severe trauma and for cancer-related pain.

Racemic ketamine has an oral bioavailability of approximately 17%. When administrated orally
in a dose of 0.5mg/kg the plasma ketamine concentration of ketamine was 40 ngml-1 (for the
same i.m. dose the plasma ketamine concentration was 150 ng ml-1 ). Oral administration is
associated with much greater concentrations of the metabolite norketamine, which may have
contributed to the analgesic effect. Orally administered ketamine undergoes extensive first
pass metabolism, primarily via N-de-methylation, resulting in low ketamine concentrations
and high norketamine concentrations in blood and tissue. The plasma levels at which
analgesia is achieved are 0.15 μg/ml following intramuscular administration and 0.04 μg/ml
after oral administration. This difference may be explained by a higher norketamine
concentration due to first-pass metabolism. This main metabolite apparently contributes to
the antinociceptive effect Oral ketamine is more potent (30 to 40%) that subcutaneous route
because first pass metabolism converts ketamine to an active analgesic metabolite.

The benefits and harms of adding ketamine to a strong analgesics pain-killers such as
morphine for the relief of cancer pain are not yet established. Only two small randomised
controlled trials suggest that when ketamine is given with morphine it may help to control
cancer pain. However, these data are insufficient to assess the effectiveness of ketamine in
this setting. So far there is little clinical evidence to support this practice,
furthermore, the The Cochrane Database of Systematic Reviews 2009 concludes that: "Current
evidence is insufficient to assess the benefits and harms of ketamine as an adjuvant to
opioids for the relief of cancer pain. More randomized randomised controlled trials are
needed".