Introduction

The concept of Intrathecal Polyanalgesia was started in 1979 following intrathecal injection of morphine. Wang et al conducted a double blind study and injected intrathecal morphine in eight cancer patients with intractable pain. The result was encouraging. They predicted that the technique may be useful in labour analgesia and postoperative pain. They also speculated that prolong pain control is possible with a drug reservoir or with an indwelling catheter¹ .The concept has travelled a long way. Now a days it is a standard protocol to treat chronic malignant and non malignant pain patients with intrathecal drugs. The growing knowledge of pain pathways, receptors, neurotransmitters, neuromodulation, and availability of newer drugs has helped to understand the subject and revolutionize treatment. The other equally important factor without which Intrathecal (IT) Polyanalgesia could never have become a success is the development of intrathecal drug delivery systems (IDDS) or various intrathecal pumps.

Indication

Main indications of intrathecal polyanalgesia are

1. Pain not subsided with comprehensive medical management (CMM). That means pain is not responding to systemic analgesic and adjuvant drugs.

2. Pain is responding to systemic analgesic drugs at the expense of unacceptable severe side effects.

Other indications are

1. Fear of addiction to narcotic analgesic drugs.

2. Patients on aggressive chemotherapy with high toxicity profile.

3. Plexopathy i.e. involvement of neural plexus.

4. Impending fracture of skeletal bones.

5. Low life expectancy.

Physiology

Pain stimulus produces impulse which travels down from periphery to Cerebral cortex via spinal cord. The spinal cord is very rich in different types of receptors for pain and analgesia. Any painful stimulation causes release of various chemical substances in the spinal cord - the neurotransmitters which carries the painful impulse in the central neuraxial system. The spinal drugs mimic or act through inhibitory neurotransmitter or they antagonize excitatory neurotransmitter. This system undergoes lot of modulation from supraspinal descending pathways, reticular activating system, limbic system and other areas CNS.

Intrathecal Polyanalgesia provides aggressive pain control by direct instillation of drugs into CNS. The dosage is usually much less than systemic dose with minimum amount of systemic drug concentration and toxicity². There are mainly two types of pain- nocicptive and neuropathic. If untreated nociceptive pain often changes to neuropathic pain and gives rise to chronic pain syndrome. Often both remains together. The mechanism is quite complex and involves sensitization of multiple different receptors, functional reorganization of receptive field in the dorsal horn of spinal cord, release of various neurotransmitters. So it can be well postulated that simultaneous delivery of multiple drugs with different mechanisms of action may be therapeutically advantageous. In many painful states there are multiple mechanisms of pain where a single analgesic drug may not be very effective and association of another drug to modulate other component of pain may be advantageous. There is evidence that several agents may not display cross tolerance and in fact prevent development of tolerance otherwise associated with the use of equipotent dose of a single drug³. Newer IDDS and newer drugs further improve the situation. Effective titration of the dosage at a short time is possible with less unanticipated and breakthrough pain. The overall effect is better analgesia with lesser side effects.

Pharmacology

Drugs commonly used are

1. Opioids

2. Adrenergics

GABA receptor agonists

Calcium channel antagonst

Local Analgesic drugs

NMDA antagonists

Miscellaneous drugs

Polyanalgesic Consensus Conference

Hassenbusch and Portenoy reviewed four hundred and thirteen physicians who use intraspinal infusion device and found out that physicians who use intrathecal analgesia and device for years do not have universal drug protocol and their usage of different drugs in different painful conditions vary according to their knowledge and experience without clear indication²⁷.To make a uniform drug policy for intrathecal administration three Polyanalgesic Consensus Conference of expert panelists have convened since 2000. These guidelines were published in 2000,2003 and 2007 and were based on “best evidence” and expert opinion. This algorhthm is for treatment of chronic pain refractory to conventional therapies. They have taken into accounts of different new molecules designed specifically for intrathecal therapeutic use, new devices (IDDS) , compatibility of the medication with the drug delivery system on “ best available evidence” inclusive of both an updated literature review and expert consensus and not necessarily by “type A evidence “ of large gold standard randomized clinical trials. The recommendations presented represent consensus of expert opinion regarding what is old and what is new and not what is standard of care. This is only to help treating physicians to formulate knowledge-based decisions when using intrathecal analgesic therapies²⁸.

The Conclusions and Recommendations of Polyanalgesic Conference 2007

Algorithm: Selection of Medications for Long-Term Intrathecal Infusion

The consensus and recommendation of a panel of experts on intrathecal polyanalgesia is to follow a definite protocol on the basis of preclinical and clinical available data. The committee recommends a six tier drug therapy for chronic pain patients. If a lower tier drug fails then the patient should get next tier drugs.

Figure 1

Line 1: Morphine (a) and ziconotide (c) are approved by the

Food and Drug Administration of the United States for intrathecal analgesic use and are recommended for first line therapy for nociceptive, mixed, and neuropathic pain. Hydromorphone (b) is recommended based on clinical widespread usage and apparent safety.

Line 2: The apparent granuloma sparing effect and because of its wide apparent use and identified safety, fentanyl (d) has been upgraded to a line 2 agent by the consensus conference when the use of the more hydrophilic agents of line 1 (a,b) result in intractable supraspinal side-effects.

Combinations of opioid + ziconotide (e) or opioid + bupivacaine or clonidine (f) are recommended for mixed and neuropathic pain and may be used interchangeably. When admixing opioids with ziconotide, attention must be made to the guidelines for admixing ziconotide with other agents.

Line 3: Clonidine (g) alone or opioids such as morphine/hydromorphone/fentanyl with bupivacaine and/or clonidine mixed with ziconotide (h) may be used when agents in line 2 fail to provide analgesia or side-effects occur when these agents are used.

Line 4: Its proven safety in animals and humans and because of its apparent granuloma-sparing effects, sufentanyl alone (i) or mixed with bupivacaine and/or clonidine plus ziconotide (j) is recommended in this line. The addition of clonidine, bupivacaine, and or ziconotide is to be used in patients with mixed or neuropathic pain.

Line 5: These agents (k), although not experimental, have little information about them in theliterature and use is recommended with caution and obvious informed consent regarding the paucity of information regarding the safety and efficacy of their use.

Line 6: Experimental agents (l) must only be used experimentally and with appropriate Independent Review Board (IRB) approved protocols.

*In patients with end of life, the panelists felt that midazolam and octreotide should be tried when all other agents in line 1-4 was tried and failed (not recommended for non malignant pain).The physician “ do no harm” mandate should be superseded by a mandate to relief pain and discomfort at the end of life.

Concentrations and Doses of Intrathecal Agents Recommended by the Polyanalgesic Consensus Panelists, 2007

Figure 2

Intrathecal cocktails need further evaluation regarding the physio-chemical properties of the mixture. As such small volume of IDDS reservoir may necessitate compounding of the drug which may itself be unsafe. Compounding means mixing of ingredients to prepare a medication for patient use, including dilution, admixture, repackaging, reconstitution and other manipulations of sterile products. Mixing of different drugs may not be stable. Morphine and hydromorphone favors ziconotide degradation though clinical effects of the combination do not reflect a decreased efficiency. Another important point in choosing a certain drug or combination takes into account of the fact whether exposure of the drugs in a device and tubings and under a surrounding temperature of more than 37degree C influence the stability of the drug or mixture. It has been also found that the degraded drugs may not necessarily be biologically inactive. The pH, tonicity , solubility, sterility of the drugs have immense importance on the success of intrathecal polyanalgesia. The United States Pharmacopia (USP) and the American society of Health System Pharmacists (ASHP) have independently issued standards on compounded sterile products.

Equianalgesic Conversion Factors for Intrathecal Medication

The conversion of opioid from one route to another is highly individualized and depends on age, pain intensity, disease. With morphine pump it is calculated as follows : Oral morphine 300 mg = Parenteral morphine 100 mg = Epidural morphine 10 mg = Intrathecal morphine 1 mg²⁹.

There is no true conversion factor for calculating dose changes from one opioids to another. There may be increased chance of respiratory depression when changing from a more lipophilic opioids to a less lipophilic opioids using conventional equipotent analgesic charts.

Best Practice Titration Recommendations

For management of cancer pain Stearns et al recommended that the titration should be guided according to patients pain level as determined by visual analog scale (VAS) and according to functional status³⁰.

Figure 3

Safety must be balanced against the need to relieve pain and suffering. The dose change can be accelerated in the cancer patients and young and robust but kept to changes weekly in the frail and the old. The polyanalgesic consensus panel recommend between 20% and 30% changes in the nonend of life population and upto 50% changes in end of life population depending on individual characteristics²⁸.

The Machine : Implantable Intrathecal device System (IDDS)

The first implanted continuous epidural infusion system was reported by Harbaugh RE et al in 1982 where two patients received epidural morphine by implanted pump . The system worked well without infection or respiratory complication³¹. Soon after the first US Food and Drug Administration (FDA) approved implantable pump (Infusaid Model 400, Norwood, MA, USA) was launched. The first generation pumps were gas driven and constant flow type. It became apparent that patients of chronic pain of various intensity with sudden increase of pain level cannot be effectively managed with a constant flow type of pump. The programmable pumps were developed which can give bolus dose along with constant flow. Predictive pain level changes due to physical activity or emotional stress as well as circadian rhythm now can be controlled by “Personal Infusion Scheme”. However this system needed further modification when unpredictive pain level changes were considered. A combination of PCA and implantable device type of thing was needed. The device so developed (SynchroMed EL, Medtronic Inc.) allows the patient to recall bolus infusion in advance of expected increase of pain (prophylactic) or in response to sudden break through pain (therapeutic). As in the usual PCA devices, the dose, infusion time, lock out interval, maximum repetitions of boluses can be programmed. Each boluses are counted as successful, rejected, unsuccessful and stored in pump memory for readeptation of basic infusion dose and bolus dose for “individualization of therapy”. The next generation (Synchromed II and PTM=Patient Therapy Manager, Medtronic Inc.) have additional features such as registering Visual analogue pain Scale (VAS) before and after a bolus. The values are stored and analyzed for reprogramming of daily doses. Optimum dose range is reflected by a reduction in daily bolus calls. In a multi centre open level registry recording 168 patients it was found that 85% patients were satisfied with PTM³².

These complicated machines have mechanical and electronic parts as well as drug reservoir. At present on account of the bulk of the machine drug reservoir may be made small. A large reservoir and a good battery life is what is aimed to be developed other than fancy programmability. The membrane pumps driven by piezo-electric mini crystals seem to meet both demands. A number of new devices like Prometra Programmable Pump System (InSet Technologies, Inc.), Medstream Programmable Infusion System (Codman and Shurtleff, Inc.), The Medallion (Advanced Bionics, Valencia, CA)etc. are awaiting for FDA approval.

Complication

Discussion and Conclusion

Intrathecal Polyanalgesia is indicated in chronic pain therapy where CMM fails.

Development of IDDS and various opioid and non opioid drugs along with growing knowledge of pain physiology made Intrathecal Polyanalgesia a highly successful modality of pain therapy in clinical scenario with very good patient acceptance. A panel of experts convened three Polyanalgesic Consensus Conferences since 2000. The last Polyanalgesic Concensus Conference was held in 2007 which has formulated an algorithm for drug selection in Intrathecal Polyanalgesia. Intrathecal baclofen a USFDA approved drug however has not been included in the algorithm for unknown reason. There are other experimental drugs like cannbinoids, calcitonin which the panelists did not include. The panel opined that clinical research on intrathecal analgesics that meets the “gold standard” of evidenced based studies has not kept pace with the growing need for innovative approaches to pain management. Vast majority of clinical experience is with the off-label use of various agents and large multicentre studies are required to establish the proven safety and efficacy. Until this is achieved the clinicians will have to depend on guidelines created from limited data and their own clinical experience. The success of intrathecal Polyanalgesia depends on issues like patient selection, screening trials, long term management issues and drug utilization. Recalling of devices by USFDA showed that intrathecal therapy is not a completely harmless technique. The evidence for IDDS is strong for short term improvement of cancer pain or neuropathic pain. Relatively strong evidence exists for the use of long term intrathecal analgesic therapy in alleviation of cancer pain. However the evidence supporting long term efficacy in persistent non cancer pain is less convincing.