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11 Articles in Volume 7, Issue #9
CES in the Treatment of Addictions: A Review and Meta-Analysis
Chronic Cancer Pain Management
Compliant Billing, Coding and Documentation for Interventional Pain Management
Critical Transition from Short-to-Long-Acting Opioid Therapy
Dextrose Prolotherapy and Pain of Chronic TMJ Dysfunction
Dysfunction and Rehabilitation of the Shoulder
Low Level Laser Therapy (LLLT) - Part 2
Placebos in Pain Management
The Good Patient: Responsibilities and Obligations of the Patient-physician Relationship
TMJ Derangement and SUNCT Syndrome Co-morbidity
Ziconotide Combination Intrathecal Therapy

Ziconotide Combination Intrathecal Therapy

Retrospective case studies in intrathecal drug therapy patients with severe chronic pain demonstrate the safety and efficacy of ziconotide in improving pain management while reducing—or halting—oral and intrathecal narcotic pain medications.

The expert panel of the 2007 Polyanalgesic Consensus Conference has recommended ziconotide as one of three medications for first-line intrathecal monotherapy. There are many times when ziconotide will be appropriate for first-line therapy, but it is currently used most often in combination. The article by Eastman and Johnson provides us more clinical insight into ziconotide use and the potential impact in reducing opioid use and improving functional outcome. I applaud the authors in their attempt to try to understand the clinical impact this drug can have in their practice. It is this type of work which should be a model for all of us who are not academics but who want to understand and apply the best clinical care for our patients.

Intrathecal drug therapy using implantable intrathecal pump and catheter systems is a safe and efficacious therapy for selective patients with chronic pain syndromes. Ziconotide (Prialt® from Elan Pharmaceuticals) represents a new class of medication that is approved by the US Food and Drug Administration (FDA) for the management of severe chronic pain in patients for whom intrathecal (IT) therapy is warranted, and who are intolerant of, or refractory to, other treatments such as systemic analgesics, adjunctive therapies, or IT morphine. It was developed to combat chronic, severe, intractable neuropathic and nociceptive pain. It is a synthetic peptide originally derived from a marine snail, Conus Magus, that binds N-type calcium channels (NCC’s) which are exclusively found on neurons. Ziconotide targets the laminae I and II layers of the dorsal horn of the spinal cord. NCC’s are concentrated here where primary afferent fibers in the pain signal pathway synapse for the first time. Ziconotide blocks calcium transportation into the presynaptic terminal. This blocks neurotransmitter release thus making pain transmission more difficult or blocking it completely. Unlike opioids, ziconotide does not suppress respiratory function. Once a therapeutic dose is reached, tolerance does not appear to develop and it does not have addiction potential.1,2

The safety and efficacy of intrathecal ziconotide has previously been evaluated in over 1,200 patients. The most frequently reported adverse events were dizziness, nausea, headache, confusion, nystagmus, somnolence, pain, memory impairment, and abnormal gait which are reversible within a few days of dose reduction or discontinuation.3, 4

In certain individuals, opioids have been implicated in causing central sensitization and, as a result, hyperalgesia. In central sensitization, the peripheral afferent nerves fire spontaneously resulting in an increased sensitivity to the dorsal root neurons. As a result of inflammation, reorganization of peripheral afferent neurons may occur. Neural fibers that do not normally transmit pain start expressing as pain transmitters so that non-noxious stimuli that normally activate these fibers results in pain transmission instead. Ziconotide blocks the N-VSCC and prevents release of the excitatory amino acid, glutamate, from the presynaptic terminal and thereby reduces the amount of stimulation at the dorsal horn neurons. It is proposed that ziconotide may unwind central sensitization over time by this mechanism.5

Ziconotide was added to the existing intrathecal therapies of thirty patients with pre-existing intrathecal pain pumps and a minimum six month retrospective evaluation was completed and the data analyzed during a period that began on August 9, 2005 and ended on November 22, 2006. Of the thirty patients evaluated, twenty-nine patients were evaluated in our Las Vegas, Nevada center and one patient evaluated in our Kalispell, Montana center, ranging in age from 29 to 79 years of age. Medications used in a variety of combinations with ziconotide included morphine, hydromorphone, fentanyl, meperidine, clonidine, baclofen, bupivacaine, ketamine, and droperidol.

It is common practice in pain management and IT therapy to utilize multiple medications having different mechanisms of action in IT pumps to provide analgesia to the patient. Adverse events from opioid utilization can be debilitating and often increase consistently over time as opioid dose requirements increase due to analgesic tolerance. Combining ziconotide with hydromorphone intrathecally may allow reduced doses of both ziconotide and hydromorphone compared to monotherapy doses while still maintaining analgesic efficacy. It is also possible that these agents in combination will be synergistic—i.e. have an effect greater than simple additivity. Lowering the doses of two agents with different side effect profiles may also result in a reduced overall side effect profile.6

Methods

Study Design. This study is a retrospective evaluation of data collected from twenty-three patients with existing intrathecal therapies that had completed six refills in thirty to forty-five day intervals of Prialt® (ziconotide) combination therapy subsequent to FDA approval of Prialt. Medications used in a variety of combinations with ziconotide included morphine, hydromorphone, fentanyl, meperidine, clonidine, baclofen, bupivacaine, ketamine, and droperidol. See Table 1 for a breakdown of these medications.

At baseline, patients completed pain questionnaires that asked them to determine their current pain level based on a scale of 1 to 10 and completed an Oswestry Questionnaire in order to determine their level of activity and functioning. Patients completed pain questionnaires at each subsequent pump refill and a follow-up Oswestry Questionnaire at their sixth and final pump refill to determine changes in activity and function.

Study Population. To be eligible for study participation, patients from two study centers in the U.S. must have been suffering from chronic malignant or non-malignant pain where intrathecal therapy was necessary. Each participant was required to have current intrathecal therapy initiated with one or more intrathecal medications through an FDA-approved infusion device and intrathecal catheter prior to study enrollment.

Potential study participants were excluded because of current pregnancy, participation in another investigational drug or device trial within the preceding thirty days, or for known hypersensitivity to ziconotide or any of its components. Exclusion criteria also included the presence of any condition that the investigators felt may impair the patient’s ability to be an active study participant, i.e., psychiatric conditions, active substance abuse, or history of poor medical treatment compliance.

IT Combination Therapy
(Patients n=23) Baseline After 6 Refills
Drug(s) n % n %
Clonidine/morphine 4 17.4% 0 0.0%
Clonidine/hydromorphone 3 13.0% 7 30.4%
Baclofen/hydromorphone 2 8.7% 0 0.0%
Baclofen/bupivacaine/clonidine/hydromorphone 0 0.0% 1 4.3%
Morphine 2 8.7% 0 0.0%
Baclofen/bupivacaine/clonidine/fentanyl/morphine 1 4.3% 0 0.0%
Baclofen/bupivacaine/clonidine/hydromorphone/ketamine 1 4.3% 1 4.3%
Baclofen/bupivacaine/clonidine/droperidol/
hydromorphone/meperidine
1 4.3% 1 4.3%
Baclofen/bupivacaine/clonidine/morphine 0 0.0% 0 0.0%
Baclofen/clonidine/droperidol/hydromorphone 1 4.3% 2 8.7%
Baclofen/clonidine/fentanyl/bupivacaine 0 0.0% 1 4.3%
Baclofen/clonidine/hydromorphone 1 4.3% 3 13.0%
Baclofen/clonidine/meperidine/morphine 1 4.3% 0 0.0%
Baclofen/clonidine/morphine 1 4.3% 0 0.0%
Baclofen/droperidol/hydromorphone 0 0.0% 1 4.3%
Bupivacaine/clonidine/hydromorphone 1 4.3% 3 13.0%
Bupivacaine/clonidine/hydromorphone/ketamine 0 0.0% 0 0.0%
Bupivacaine/clonidine/morphine 1 4.3% 0 0.0%
Bupivacaine/morphine 1 4.3% 0 0.0%
Clonidine/hydromorphone/ketamine 1 4.3% 1 4.3%
Droperidol/hydromorphone 1 4.3% 1 4.3%
Hydromorphone 0 0.0% 1 4.3%

Total

23   23  
Table 1. Intrathecal drugs used in combination with ziconotide.

Dosing of ziconotide included the utilization of a 100 mcg/ml vial. Ziconotide has an inherent property that is attracted to metal making an initial “rinsing of the pump” with a solution of ziconotide necessary (See Addendum). This prevents a decreased dose of ziconotide from reaching the intrathecal space after the initiation of ziconotide therapy.

Initial doses of ziconotide ranged from .25 mcg to .5 mcg per day. Patients age 64 and younger were started at a dose of .50 mcg per day, while those patients whose age was 65 and older were initiated at .25 mcg per day. At the time of initial ziconotide administration, 50% of the study participants had their daily rate of base drug (morphine, hydromorphone, fentanyl) decreased by a range of 1 to 10%. The final mean daily dose of ziconotide after six refills was 1.76 mcg per day as seen in Figure 1.

End Points And Measurements

Efficacy Measures. The primary outcome measure was the mean percentage of change in VASPI scores from baseline to termination of study participation following six pump refills at thirty to forty-five day intervals. Study participants had an overall decrease in VASPI scores that ranged from 20% to 80%, with a mean 43% decrease in VASPI scores and no increase in concomitant opioid use.

Safety Measures. All patients were monitored closely for adverse events. No patient-initiated telephone reports of adverse events were made during the study period. All patients were followed at thirty to forty-five day intervals and patients were not only asked about side effects at clinical visits, but also filled out pain questionnaires that asked specifically about adverse events.

Figure 1. Daily ziconotide (Prialt®) dosing titration from pump refill 1 through 6. Figure 2. VASPI scores measured at baseline and every 30 to 45 days through 6 refills.

Statistical Analysis. The initial sample size was thirty patients receiving ziconotide in combination therapy. During the course of the six pump refill study period, seven patients dropped out for various reasons. Thus, twenty-three patients completed their six pump refill participation allowing us to fully evaluate their VASPI scores and side effect profile at each pump refill throughout the study timeframe.

Results

Patient Disposition. Enrollment of the first study participant occurred on August 9, 2005, with the last patient completing the study on November 22, 2006. Patients, ranging in age from 29 to 79 years of age, were enrolled in two U.S. study centers with the mean age of 57.8 years. Of the thirty patients enrolled, nineteen (63.3%) patients were female, and eleven (36.7%) male. Of the thirty overall patients enrolled, twenty-nine patients were Caucasian and one was African-American. Our LasVegas, Nevada center enrolled 29 patients and the study center in Kalispell, Montana enrolled one study participant.

All thirty of the study participants received ziconotide in combination with their existing intrathecal regimens. Thirteen patients had pumps with morphine as the base drug, fifteen had hydromorphone as a base drug, one patient had fentanyl as a base drug, and one patient contained both morphine and fentanyl.

Adverse events were low as evidenced in Table 3. Of the thirty patients who started the study, seven participants did not finish. Of these seven patients, only three reported side effects. Two reported psychological (“mood swings” and “going crazy”) symptoms, and the third reported over-sedation. The over-sedation and one psychological symptom were reported within the first month and the remaining psychological symptom was reported after the third refill.

All three participants reported their side effects as mild and felt that they could have continued, but chose not to continue their participation. One of the three had 100% pain relief and after three months off, requested to be restarted on ziconotide. This patient unfortunately died following complications of surgery prior to re-initiation of ziconotide.

Four patients ended their participation due to other situations other than adverse events. Two of these participants relocated to different pain practices before the study period ended with both improved on ziconotide without side effect at their time of departure. The third participant had repeated drug overdoses from injectable Meperidine elsewhere. Her pump was surgically removed for patient-safety concerns thus ending her participation in the study. Finally, the fourth patient died under hospice care with a diagnosis of pancreatic cancer before ending her study participation.

Of the patients discontinuing ziconotide, none experienced symptoms of withdrawal. Three patients reported side effects with no other complications (mild or severe) being reported in any other patients. No hypersensitivity to ziconotide was observed.

At baseline, the twenty-three patients completing the study had a mean VASPI score of 9 on a 1 to 10 scale. From baseline to the end of the six pump refill study period, mean VASPI scores improved 43% from a 9.04 [standard deviation of 1.30] to a mean of 5.13 [standard deviation of 2.26] and using a paired t-test this was statistically significant with a P value of less than .0001. Pain improvements ranged from 20 % to 80 % in twenty-one patients with two patients reporting no improvement in their overall pain after six pump refills in this study. The therapeutic effect, improvement in VASPI scores, was statistically significant as shown in Figure 2.

Secondary Efficacy. A decrease in oral narcotic consumption was seen with patient overall mean narcotic prescriptions totaling 1.69 prescriptions at baseline and 1.39 prescription at the end of six pump refills (see Table 4). Initial baseline intrathecal opioid doses were hydromorphone 7.9 mg (6.89 when converted from morphine) and fentanyl 1,500 mcg per day.

Following a total of six pump refills, the ten patients that changed from morphine to hydromorphone had a daily intrathecal dose that averaged a mean 2.44 mg per day. The patient with fentanyl as a base drug decreased to 1,100 mcgs per day and the initial hydromorphone group decreased to 6.65 mg per day.

Overall response to ziconotide by the ten patients in the morphine group had six patients with an increase in their daily morphine dose, two patients with a decrease in their daily morphine dose, and two patients that had no change in their morphine dose over 4 pump refills. The change for these ten patients from morphine to hydromorphone provided them with better overall pain relief at a lower dose of intrathecal narcotic. This change also resulted in improved pain control over forty-five days between pump refills for all patients with hydromorphone versus thirty days of varied pain levels while in combination with morphine.

Of the twelve patients in the hydromorphone group, two of these patients had a dose increase in their daily hydromorphone dose, and ten patients experienced a daily hydromorphone dose decrease. The sole patient with fentanyl as a base drug in combination with ziconotide experienced a decrease in daily dose.

The main outcome measure was pain reduction measured by VASPI scores. A direct result of pain reduction was improvement in activity and function. At the patients’ clinical visits and intrathecal pain pump refills, their oral and written reports about pain levels and functionality were impressive and is reflected in Figure 2 and Table 6.

Discussion

Of the thirty patients evaluated retrospectively, all patients received ziconotide. The average final dose for the twelve patients initiated with hydromorphone as their base drug was 6.65 mg per day—down from a daily dose of 7.9 mg at baseline.

Ten patients initiated on morphine and later converted to hydromorphone averaged 6.89 mg per day at baseline and 10.78 mg per day up to four months before being converted. The ten patients who were converted saw a mean daily average of 2.44 mg of hydromorphone. The mean daily average dose of hydromorphone for the patients who ended their six refills of participation on hydromorphone was 4.73 mg per day. One patient on fentanyl started at 1,500 mcg per day and ended at 1,100 mcg per day after six pump refills.

Demographic and Baseline Characteristics
Age, mean (range), y 57.8 (29-79)
  n %
Sex: Male 11 36.7
  Female 19 63.3
Race: Caucasian 29 96.0
African American 1 4.0
  Mean Range
Baseline VASPI score, cm 9.0 4-10
Pain etiology    
  Nonmalignant 30 100.0
Pain mechanisim*    
  Neuropathic 30 100.0
  Degenerative 23 76.7
  Sympathetically maintained 3 10.0
  Other 4 13.3
Failed back surgery syndrome n=17 %=56.7
Table 2. Patient demographics and baseline characteristics of the 23 patient evaluable sample.
Patients with any adverse event 3
Patients with serious adverse events 0
Emotional Disturbances 2
Somnolence 1
Table 3. 10% of the 30 patients who started the study reported adverse events; 90% were side-effect free.
Opioid Consumption
  Baseline (n=23) Month 6 (n=23)
  Mean n Range % Mean n Range %
Oral Opiods 1.69 0-3 1.39 0-2
IT Opioids 1.1 1-2 1.1 0-2
Table 4. Changes in oral opioid consumption over 6 months.
Changes in Intrathecal Consumption
  Dose
decreased
Dose
increased
Dose stayed the same
Morphine (mg qd) 2 6 2
Hydromorphone (mg qd) 10 2 0
Fentanyl (mcg qd) 1 0 0
       
       
Table 5. Changes seen in base intrathecal drug over the 6 pump refill study period.

Mean VASPI scores were 9 at baseline and, after six refills of ziconotide combination therapy, was 5.1—a 43% improvement. One patient received complete pain relief with the combination therapy but, due to side effects, elected to discontinue study involvement. Two patients received no pain relief during their six pump refill period of treatment with ziconotide in combination with other existing intrathecal medications.

Conclusion

Intrathecal Ziconotide (Prialt®) provided clinically and statistically significant analgesia in patients with chronic non -malignant pain with pre-existing intrathecal pumps and existing therapies. This study demonstrates statistical and clinically significant improved analgesia in patients using ziconotide in combination with other intrathecal therapies.

Functional Improvement
Pain Intensity 82.6%
Personal care 78.3%
Lifting 60.9%
Walking 60.9%
Sitting 78.3%
Standing 69.6%
Sleeping 91.3%
Sex life 30.4%
Social life 78.3%
Traveling 73.9%
Table 6. Functional improvements seen in the 23 patient sample from baseline through 6 pump refills.

Thirty of the most complex and treatment-resistant patients in our practice were included with all but two patients responding to their ziconotide combination therapy. Of these, seven dropped out for various reasons leaving twenty-three evaluable patients for this study. These patients in a large pain practice had significant decreases in pain by the simple addition of a potent non-narcotic analgesic drug—while adverse events were very low and oral and intrathecal narcotic pain medications were halted or decreased.

The ultimate goal in pain management is to decrease the pain levels that patients experience and, if possible, improve their quality of life and level of function. The fact that patients had an overall mean improvement in pain scores of 43%, side effects of only 10% and significant improvements in functionality would indicate the efficacy and overall value of intrathecal ziconotide in combination with other intrathecal therapies. As such, further studies of this exciting new therapy are certainly indicated.n

Addendum

Ziconotide has an inherent property attracting it to metal making an initial “rinsing of the pump” with a solution of ziconotide necessary.

Following a standard pump rinsing protocol, a total of 6 cc’s are drawn up into one syringe. Utilizing a 100 mcg/ml, 1 ml vial of Prialt, ½ cc of Prialt is drawn up along with 5 ½ cc’s of normal saline. Once mixed, three 2 cc flushes of the pumps drug reservoir is done after having emptied the pump completely of its contents.

Acknowledgements

We thank Michael Facio and Shelli Lara, both independent contractors, Las Vegas, for data management and statistical analysis. We also wish to thank Audrey Suh, PharmD, Medlogix, for preliminary data management and statistical analysis in preparation for Elan Pharmaceuticals, Inc., National PRIALT Investigator Meeting, Sept. 29-30, 2007 in New York City.

Last updated on: January 5, 2012
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