1. To review the physiology of pain mechanisms, looking at
new concepts from modern molecular biology.
2. Contrast the actions which occur locally and centrally.
3. Look at some of the new avenues of research for more
specific analgesic agents.
4. Review recent reports of new uses of local anaesthetics in
the treatment of chronic pain.
5. Look at some of the new promising centrally-acting drugs
for controlling chronic pain.
6. Review the indications and the protocol for the use of
narcotics for pain of non-malignant origin.
ECCLESIASTES 1:9 ...and there is nothing new under the sun. Is there a thing of which
it is said, "See, this is new"?
No - wait a minute - don't leave yet!
There have been some exciting developments in our understanding of the mechanisms of pain
perception.
The classic teaching on pain mechanisms was hauntingly simplistic:
This old picture of "fixed property" nociceptors implanted in damaged tissue,
passively detecting cell breakdown, no longer holds.
Let us look at what the power of modern molecular biology tells us that makes us
re-evaluate our understanding.
Tissue damage:
The CNS is informed of tissue damage by afferent fibres in 2 quite different ways:
In the dorsal horn are integrated groups of cells, initially thought to be solely
inhibitory. It now appears there are equally powerful excitatory/facilitatory mechanisms.
The chemistry and role of these excitatory mechanisms is being discovered, raising the
possibility of therapy for such conditions as deafferentation states.
The main processes believed to contribute to chronic pain biochemically are illustrated in figure 1 - BJA 1995;75:146
These can be divided into:
Inflammatory mediators trigger prostanoid production through the cyclo-oxygenase (COX)
pathway, and leukotrienes through the 5 lipo-oxygenase pathway.
2 Isomers of COX were recently described:
We are all aware of the side effects of NSAIDS - so great interest in developing a
selective COX2 inhibitor with a better side effect profile. Prototype inhibitors block
hyperalgesia in rats without Renal/GI side effects.
There are no current leukotriene receptor antagonists with analgesic properties.
These are released from WBCs and immune cells early in inflammation. Cytokine
suppressive antiinflammatory drugs (CSAIDS) are being discovered which inhibit cytokine
production. These drugs show promise in both acute and chronic pain models.
In the field of neuropathic pain, NSAIDS are ineffective and opioids relatively so.
Drugs which reduce membrane excitability eg. Local anaesthetics and antiarrhythmics are
showing increasing utility.
Studies, mainly by Devor et al, have shown that spontaneous ectopic activity develops in damaged sensory neurones and dorsal root ganglia.
A number of carefully executed clinical studies have shown that systemically administered local anaesthetics may have analgesic properties specific to pain states resulting from damage to nerve tissue.
Analgesia is attained in the absence of motor or sensory conduction blockade, at doses without toxic effects.
Most recently Chaplan et al (Anesthesiol 1995) demonstrated that:
A slow Na+ channel has been discovered which may offer an attractive target for
novel analgesic drugs.
Immune cells can produce endogenous opiates during inflammation. Experiments with inflammatory and neuropathic pain models suggest these opiates exert an effect on primary afferent nerve terminals and sympathetic nerves.
This raises the possibility of developing peripherally acting opiates as analgesics
which would lack the sedative and psychotropic effects of existing opiates.
Include:
3 Major receptors - NK1, 2, and 3
NK1 receptors predominate in human CNS & substance P is the preferred agonist.
In the spinal cord, substance P-mediated transmission -- long-lasting depolarisation of dorsal horn neurones. This -- long-lasting facilitation of transmission (wind up) in the nociceptive pathway - a major factor in producing functional hyperalgesia.
This enhanced spinal excitability produced by substance P is inhibited by non-peptide NK1 receptor antagonists.
NK1 antagonists have not - so far - been reported to have marked effects on cns function, apart from their analgesic and anti-emetic actions.
Clinical trials are currently under way, and such drugs should soon become available
for more general clinical use as analgesics.
Does more than make you gallbladder squeeze!
NMDA receptor antagonists prevent the "wind up" phenomenon in the spinal cord.
Ketamine blocks the ion channel associated with the NMDA receptor. It is an effective analgesic alone, or in conjunction with morphine, and has been successfully used in patients with neuropathic cancer pain unresponsive to massive doses of oral, iv, and epidural narcotics 5 - 100 mg/hr by iv or sc were used for up to 13 months duration.
Currently the selectivity for the nociceptive pathway is insufficient for analgesia to
be produced without some unwanted side effects. However this may not be insurmountable,
when used in adjuvant doses, there has been a concurrent decrease in narcotic requirements
and often an improvement in mental clarity.
Currently, despite the aforementioned potential therapies, we are not infrequently left with a patient unresponsive to all non-narcotic methods of pain relief. (here, I include non-pharmacologic Rx eg. TENS, psychotherapy, behaviour modification, rehabilitation, physio, OT etc)
A decision has to be made as to the suitability of institution of chronic narcotic
therapy. This is controversial for obvious reasons. Firm guidelines for this approach have
not been established, and docs fear scrutiny by regulatory agencies.
A growing body of evidence indicates selected patients may obtain long term
control of symptoms with narcotics, with simultaneous enhancement of physical and
psychological function.
| Portenoy & Foley | 83% +ve response |
| Zenz | 4% tolerance |
| Burchman & Pagel | 3% abuse |
In these reports there were defined treatment objectives:
Some jurisdictions (Pagel, Wisconsin) have implemented a formal treatment agreement between patient and physician designed to serve and monitor the continuing medical requirements of the patient (and perhaps to protect the physician from repeated investigation by regulatory authorities U.S.).
Physician:
Patient:
Statement of Objectives:
Exclusion Criteria:
Other Factors:
Bulk of patients enrolled:
**The reports were from a V.A. Hospital system, where controls may have been tighter
than attainable in a Canadian system.
Transdermal delivery systems for narcotics can reduce the potential for abuse - can't
get the same highs as with po, iv, rectal etc. our experience with transdermal fentanyl
patches has been encouraging - RSD, PHN, LBP.
There is no place for narcotics in the management of patients with pain of
non-malignant origin. T / F?
Specialist consultation preferred before placing a patient on long term oral narcotic
therapy T / F?
Neuropathic pain is untreatable. T / F?
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