Drug
Range of doses
Morphine
1.0–20 mg/day
Hydromorphone
0.5–25 mg/day
Sufentanil
10–100 μg/day
Bupivacaine
6–20 mg/day
Clonidine
250–2,000 μg/day
Thus, compounding by a trained pharmacist will be needed. The goal is to concentrate these drugs to twice the daily dose, so that the 20 ml programmable pumps may be programmed to deliver 0.5 ml/h. In this way, patients will need pump refills monthly and it will not be a burden to their quality of life by having too frequent visits to the pain specialist’s office. The steps that we use to implement the therapy are:
1.
Step 1:
(a)
Opioid + bupivacaine:
MS 3–25 mg/day or hydromorphone 0.5–15 mg/day
**6 mg of MS/day = 1 mg of hydromorphone/day
Bupivacaine: 6–20 mg/day
(b)
Opioid + clonidine:
Clonidine: 250–2,000 μg/day
2.
Step 2: Opioid + bupivacaine + clonidine
3.
Step 3: Ziconotide:
(a)
Initiate therapy with ziconotide at a dose of 2.4 mcg/day (0.1 mcg/h) and titrate to patient response
Rinse the pump with 2 ml of the 25 mcg/ml solution three times and then fill the pump with the balance (16 ml)
(b)
Titration increments should not be more than 2.4 mcg/day or more frequent than once per week
(c)
Maximum recommended dose: 19.2 mcg/day (0.8 mcg/h)
4.
In particular situations, the use of morphine + ziconotide may be an alternative [10]. However, the limitations include the following:
(a)
The benefit of a trial does not exist, as ziconotide may not be administered in the epidural space. Consequently, the patient will need progressive titration once the implanted system is in place.
(b)
Patients may not allow the practitioner to carry out a titration protocol over 4–6 weeks since:
(c)
Starting dose for ziconotide is 2.4 mcg/day with weekly increases of not more than 2.4 mcg/day
Therapeutic effects are not usually seen until a dose of 8–10 mcg/day is reached.
Recently, the option to coadminister ziconotide with morphine has emerged. A phase II, open-label, multicenter study of combined intrathecal morphine and ziconotide as add on therapy in 26 patients with noncancer pain showed that the mean improvement in pain, as judged by visual analog scale measurements was 14.5 % from baseline to week 5 [10]. Moreover, there was a mean decrease in opioid therapy of 14.3 % at week 5. Treatment-related side effects included mental confusion, dizziness, abnormal gait, hallucinations, and anxiety. Consequently, both the mean pain improvement and the mean opioid sparing effect are produced by the use of this agent where clinically insignificant. However, the maximum dose of ziconotide used in this study was 7.2 mcg/day and that may explain the marginal results.
If triple therapy with an opioid, bupivacaine, and clonidine at optimal doses is not working or one considers the need to implement therapy with ziconotine, then evaluation for catheter obstruction, disconnection, catheter migration, or pump malfunction is a must. In doing so, consider the following possibilities:
1.
Pump: Computer program analysis for volume and the volume present within the pump needs to be within 10 % of each other, otherwise pump failure is suspected due to:
(a)
MRI Effects (Medtronic Medical Device Correction, August 2008).
There is a potential for a delay in the return of proper drug infusion after a MRI affecting all SyncroMed pumps. Moreover, with SynchroMed II pumps, there is the potential for a delay in the logging of motor stall events after MRI. Although the reported incidence of these phenomena is very low (0.014 % and 0.11 % respectively) it is important to interrogate all the pumps after the MRI, to spare patients from not receiving medication. This is particularly important for SynchroMed pumps, as a “Pump Memory Error” may be generated and the pump will NOT restart infusing unless it is reprogrammed. In contrast, the SynchroMed II may continue infusing even though the interrogation may show a stall state. In either case, the pump will alarm in the face of a stall phenomenon.
(b)
Missing Propellant within the pump: Synchromed® II Missing Propellant. Models Affected: 8637–20, 8637–40 (Medtronic Medical Device Recall—May 2008)
(c)
Synchromed® EL pump motor stall due to gear shaft wear (Patient Management Information (Medtronic, August 2007)).
2.
Catheter: A myelogram performed through the diagnostic port of the pump will be needed to determine if there is obstruction, disconnection (Medical Device Safety Alert—June 2008: Proper Connection of Sutureless Connector Intrathecal Catheters Models Affected: 8709SC, 8731SC, 8596SC, 8578), and the position of the tip of the catheter. When performing a myelogram through the diagnostic port of the pump, remember that this only accommodates a 25-gauge Huber needle. Moreover, consider:
(a)
The dead space of the catheter when injecting the contrast medium: 0.196 ml [89 cm total catheter length (81.4 cm for the spinal segment + 7.6 of the catheter interface with the sutureless connector) × 0.0022 ml/cm catheter volume for the model 8709 SC]
(b)
The need for a bolus dose after the study is completed, as the catheter will be filled with contrast medium. Consequently, at a programmed rate of 0.5 ml/h it will take 9.4 h for the pump to clear all this volume resulting in inadequate pain control and possibly opioid withdrawal symptoms.
When performing pump’s diagnostic port injections, one needs:
To withdraw enough amount of cerebrospinal fluid/therapeutic solution prior to injecting contrast medium to remove all the volume of the drug within the catheter and avoid giving the patient a bolus of the medications in use. If this was not performed, up to 0.196 ml of solution could be pushed alone with the contrast medium. Likewise, we suggest that one should aspirate the fluid with a 3 ml syringe at a very low negative pressure to avoid turbulent flow and the risk of leaving medication within the catheter (cavitations phenomenon). We usually aspirate a total of 3 ml of fluid, as this should contain all the medication left in the catheter’s dead space and some CSF.
A bolus dose should be programmed after the myelogram to clear the catheter’s dead space containing contrast medium at this point. By doing so, one avoids leaving the patient without intrathecal treatment for periods of 16–20 h depending on how much catheter was implanted.
Clinical Studies
A recently published multicenter prospective randomized clinical trial by Smith, et al., compared intrathecal therapy to comprehensive medical management (CMM) after 1 month of therapy in 202 cancer patients with refractory pain [11]. The primary outcome measure was a 20 % improvement in analgesia, as measured via a 0–10 visual analog scale. Additionally, side effects change based on the National Cancer Institute’s common toxicity criteria. There was a slight trend toward better analgesia in the intrathecal group but this difference did not achieve statistical significance. In contrast, there was a statistical difference in the side effect profile of those patients randomized to the intrathecal group. The two side effects where the therapy had its greatest impact were constipation and level of consciousness. After a 6-month analysis, there was also a trend towards an increased survival in the intrathecal group (54 % versus 37 %). Even though the number of patients who were alive at the end of the analysis was small, this difference is about a 25 % increase in survival in the patients randomized to the intrathecal group when compared to the CMM group.
A longitudinal prospective analysis of 30 crossover patients that received intrathecal therapy found significant decreases in pain scores and drug toxicity (27 % and 51 %, respectively) [12]. Median survival was 103 days after crossover to an IDDS, which was similar to that of patients in the randomized controlled trial [12].
The cost of implementing intrathecal therapy is initially high, because of equipment acquisition cost. In contrast, the cost of implementing long-term epidural therapy is low. Two studies evaluated the cost of implementing therapy with these two modalities. These analyses show a “break even” point at approximately 3 months [13, 14]. Thus, epidural therapy becomes very expensive after 3 months, and is one of the reasons to limit its use in patients with survival expectations of less than 3 months.
Clinical Guidelines
A consensus panel was recently published to update recommendations on the use of intrathecal medications in chronic noncancer pain [15]. Their goal was to:
1.
Review the conclusions and guidelines of the Polyanalgesic Conference 2000 and Polyanalgesic Conference 2003.
2.
Evaluate the current guidelines for IT drug infusion.
3.
Review survey responses of fellow peers in the field of IT analgesics for pain management and use the findings to guide discussion during the conference.
4.
Review preclinical and clinical data relevant to IT analgesics published since 2000.
5.
Formulate consensus opinions on critical issues for IT polyanalgesic therapy.
6.
Modify and update the IT analgesic drug selection algorithm, as appropriate, based on “best evidence” from published data and expert consensus opinion.
7.
Identify areas, including promising under-researched and experimental analgesic agents, for future evidence based research that will advance the clinical practice of IT drug infusion therapy.
8.
Disseminate the consensus opinions and primary conclusions of the expert panelists to the medical community through data-driven articles published in appropriate peer-reviewed biomedical journals.
Although the consensus limits its conclusions to the noncancer population, there are five issues that are important to discuss, in light of the recommendations given in this review:
1.
Hydromorphone equianalgesic doses
2.
Hydromorphone maximum dose
3.
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