Implantable Intrathecal Pumps for the
Treatment of Noncancer Chronic Pain in
Elderly Population: Drug Dose and Clinical

William Raffaeli, MD, PhD* • Donatella Righetti, MD* • Alessandro Caminiti, MD* • Alessandro Ingardia, MD† • Marco Balestri, MD* • Lucia Pambianco, MD‡ • Guido Fanelli, MD, PhD‡ • Francesca Facondini, MD† •Pantazis Pantazopoulos, MD† *Pain Therapy and Palliative Care Unit, “Infermi” Hospital, Rimini, Italy; Department of Anesthesiology and Intensive Care Rimini, Italy; and School of Specialization in Anesthesia and Resuscitation, University of Parma, Parma, Italy ABSTRACT
Objective. This study aims to assess long-term follow-up of efficacy and quality of life for 34 geriatric patients (10 men, 24 women, mean
age 72.3 ± 11.6 years) with intrathecal (IT) drug delivery systems (IDDS), implanted between 1994 and 2002, for the treatment of severe
noncancer chronic pain. Methods. Patients equal to or older than 64 years, who had no pain relief after administration of a placebo
injection (subcutaneous saline), and who responded positively to an IT trial (morphine and bupivacaine at low doses) with pain relief
greater 70% without intolerable adverse effects were included into our study. Clinical assessment forms and questionnaires assessing
pain intensity, adverse events, complications, concommitent use of analgesics, and doses of IT drugs administered were filled out by
our patients prior to and after IT drug delivery implantation. Results. Pain intensity was substantially reduced (60%) at three-month
follow-up after commencing IT therapy and was consistently reduced at 48-month follow-up. The mean visual analog scale (VAS) value
decreased from 8.09 (± 1.25) before implantation to 1.68 (± 0.63) after implantation at 48-month follow-up. This benefit, at 48 months,
was achieved using mean low doses of IT morphine and bupivacaine, 1.03 ± 0.61 mg and 1.15 ± 0.58 mg, respectively. Only two out of
34 patients (5.9%) had complications related to the implantation procedure, itself. Side-effects of therapy were reported by 50% of the
patients, the most frequent being constipation (34.4%), drowsiness (21.9%), nausea (21.9%), and urinar y retention (18.8%). No side-
effects of therapy resulted in removal of the IDDS. Conclusion. The use of IT drug delivery through IDDS for the treatment of
non-cancer- and cancer-related pain in geriatric patients is successful.
KEY WORDS: IT therapy, noncancer chronic pain, pain management.
drug administration or for those who do not tolerate high Recently, there has been an increasing interest in the use doses of orally administered opioids because of systemic side- of IT therapy for pain therapy for patients who do not effects. Reports have been published describing the treatment receive adequate pain control with traditional methods of of cancer and noncancer pain with this technique (1).
Submitted: February 15, 2006; accepted: July 11, 2007. Address correspondence and reprint requests to: William Raffaeli, Pain Therapy
and Palliative Care Unit, “Infermi” Hospital, Rimini, ITALY. Email: [email protected]
2008 International Neuromodulation Society, 1094-7159/08/$15.00/0
There are several clinical advantages to intrathecal (IT) and dynamics of a drug (12). In particular, the reduction therapy for pain control. Because there is a slow replace- of body water level results in a reduced distribution of ment of the cerebrospinal fluid (CSF) over time, morphine, hydrophilic drugs, such as morphine. Similarly, the age- when delivered IT and its metabolites, especially morphine- related reduction of plasma proteins causes an increase in 6-glicuronide, provide prolonged analgesic (2 – 4). The the concentration of active drug and, hence, a reduction use of IT bupivacaine for the treatment of noncancer in drug dosage needed. Moreover, the decrease of renal chronic pain has also been widely described and studied and hepatic output requires an adjustment of drug dos- and has been shown to be free of bone marrow toxicity and to have positive synergy with opioids (5,6). Because It was the aim of our study to evaluate and assess the use local anesthetics and opioids work on differing analgesic of IT opioids combined with IT local anesthetics for pain systems, low doses of these agents, when added to each treatment in a geriatric population. It was the secondary other IT, provide analgesic synergy (7). Moreover, the use aim of this study to evaluate the mean lowest IT dose of a low dose of bupivacaine when added to IT morphine possible in this study group, an important fact to ascertain allows for a low dose of morphine, thereby reducing the because, as a group, the elderly have more side-effects to incidence of opioid-related side-effects (8).
pharmacologic management than a similar group of Although morphine is the gold standard agent used for IT therapy, experts in the field of IT therapy today use avariety of drug combinations, such as morphine/bupivacaine, Materials and Methods
hydromorphone, and morphine/clonidine (7,9), but aclear standard for the correlation of a specific combina- tion of drugs to the treatment of a specific type of pain is We performed a retrospective analysis of efficacy and still lacking. An effective dose of opioids is variable safety data on 34 geriatric patients (ages 65 – 86 years) and individual to the needs of each and every patient; suffering from chronic non-cancer-related pain, who however, the effective dose of any one opioid often underwent implantation with IDDS systems for IT therapy reaches high levels for various reasons including syndrome- between the years, 1994 – 2002. All implantations were specific opioid resistance, receptor phenotype-determined carried out under local anesthesia. The IDDS systems used resistance, and/or tolerance to the opioid delivered.
included Archimedes (Anschütz, Kiel, Germany) in two Appropriate patients are selected for IDDS using IT/ patients, Tricumed (Anschütz) in six patients; Isomed epidural trials either by single shot injection or titration (Medtronic Inc., Minneapolis, MN, USA) in 24 patients through an implanted catheter until effective dosage is and Synchromed (Medtronic Inc.) in two patients. In this group, there were 12 patients with peripheral neuropathic The IT administration of low-dose agents for the attain- pain (diabetic neuropathy or complex regional pain ment of satisfactory pain control is particularly important syndrome type I), 11 with nociceptive pain (osteodegener- for the geriatric population. Nowadays, the number of ative spinal stenosis and low back pain) and nine with elderly people and the average age of the population are neuropathic-nociceptive pain (failed back surgery syn- increasing. The elderly often suffer from age-related drome). All patients reported a visual analog scale (VAS) diseases such as vascular cardiopathies, cerebrovascular intensity of greater than six for at least one year and had diseases, osteoporosis, and arthrosis, which are, in-of- failed more conservative therapies to control basal pain themselves, allergenic (10) and from pneumonias, diabetes, levels and phases of acute pain. Patients with nociceptive peripheral arterial diseases, and fractures, which generate pain (11) and nociceptive-neuropathic pain (9) had further pain (11). These diseases result in serious disabilities received prior infiltrative therapies such as intra-articular and limitation of patients’ physical, cognitive, and social infiltrations and peridural blocks with corticosteroids and activities, resulting in loss of the autonomy and worsening anesthetics and oral opioids without any benefit or the of their quality of life. For this reason, it is of primary development of severe, intractable side-effects. Seventy importance to find an efficient analgesic therapy for the percent of the patients with nociceptive pain and 30% of elderly that avoids pharmacologic interactions with other the patients with neuropathic pain did derive benefit from medications used by patients for the treatment of their their oral opioids; however, the development of side- comorbid diseases that result in unwanted effects and effects such as over sedation resulted in discontinuance of the therapy (12). The group with neuropathic pain (12) It is also well-established that the elderly (older than also trials for spinal cord stimulation without benefit (5), 64 years) need lower doses of drugs to achieve the same or had developed tolerance (7) to the effect of spinal level of efficacy that younger patients need. The aging cord stimulation (after around six years). Transcutaneous process, indeed, involves a series of metabolic modifications electrical nerve stimulation was used in four patients suf- that result in important alterations of the pharmacokinetics fering from low back pain. All patients in our study group responded positively to an IT morphine infusion trial, (0.5%) 0.125 mg, given IT, or a paraspinous subcutaneous reporting a reduction of greater than 70% from the initial administration of saline solution (2 mL).
This trial for efficacy and safety lasted seven days.
The following patients were excluded from our study: Placebo or morphine/bupivacaine IT injections were administered to patients on days 1, 3, and 7 of the trial.
• Patients with a personality disorder; Patients were considered to be positive responders to IT • Patients who underwent implantation with IDDS for analgesia if they received pain relief greater than 70% after administration of morphine and bupivacaine, and • Patients suffering from cancer pain or central neuro- less than 30% after injection of the placebo. The dose of pathic pain (central neuropathic pain is known not to morphine/bupivacaine that provided relief of pain during be responsive to opioids and local anesthetics); the trial was the initial dose used at implantation.
• Patients unresponsive to a trial of efficacy for IT therapy At each subsequent visit to our pain unit, we evaluated the patient’s residual pain complaint and modified the • Patients who developed intolerable adverse effects dose of morphine/bupivacaine using the following (especially those affecting respiration and diuresis) during • Our initial dose of morphine was 0.1 mg/day that was • Patients allergic to opioids or local anesthetics; increased to a maximum dose of 1.0 mg/day if the • Patients suffering from chronic abuse of drugs that act patient had significant residual pain.
• If the pain was not adequately controlled at a dose of • Patients who required clonidine or other adjuvant 0.5 mg/day of morphine (evaluated as a VAS 0 –10 other than bupivicaine for control of pain. Clonidine reduction of less than three points), 0.5 mg/day of was administered in association with morphine to bupivacaine was added to morphine infusion.
patients who developed tolerance to morphine or who • The bupivacaine dose was increased by 0.25 mg/day had pruritus as an adverse event to the delivery of IT until a reduction of at least three points in VAS was morphine. Bupivicaine, however, was administered as observed. After two increases of bupivacaine dosage, if the an adjuvant to morphine when VAS scores were not VAS reduction was still less than three points, then the controlled during the IT trials with morphine alone, in dosage of morphine was increased (maximum dosage particular, when the VAS was reduced less than 50%.
We limited this retrospective analysis to patients receiving Patients were generally evaluated monthly, when they morphine and bupivacaine because the addition of patients came to the clinic to refill the pump. Extra visits were with other combinations of agents would have complicated made every time the patient did not achieve a satisfying our analysis, rendering interpretation of results almost pain control, in this case a change in the drug dosage was impossible. Our study was limited to answering the allowed. The data shown in this paper were collected questions of whether IT morphine or IT bupivacaine/ only at selected time points (as described in the next morphine was efficacious in this population of elderly paragraph) from the clinical files of patients.
patients at doses that were both efficacious and low.
Using questionnaires, the following variables were Before implantation of a permanent IDDS system, a evaluated by our clinicians at each visit: pain intensity trial was performed to assess efficacy and tolerability (VAS, 0 –10), dose of IT drug (morphine or bupivacaine), of intraspinal analgesia infusion. We, as is our usual and incidence of side-effects, and complications. Each variable customary procedure, performed the trial with single was evaluated at different time points: before implantation intrathecal injections of drug at L2 – 3 via a 27-gauge (t ) and at 3, 6, 12, 18, 24, 36, and 48 months after Whitacre spinal needle (Becton Dickinson Caribe Ltd., implantation (t –t ). At each time point, the mean and the Juncos, Puerto Rico) in the sitting position. The clinician standard deviation of VAS and dosage of drugs used were performing the trial also evaluated whether the placebo injection or the injection of the active agent resulted inpain relief, according to the customary procedures of our department, but was not involved in data recording and/ For VAS values and drug doses used, the means and or treatment for opioid-related side-effects. All patients standard deviations were computed. A paired t-test was and doctors, who recorded the data and treated therapy- used to analyze the significance of changes observed in related side-effects, were blinded to whether a placebo or VAS values and morphine and bupivacaine doses at each active agent was administered. Agents used for this trial time point in respect to the previous time point (p < 0.05 included either morphine 0.1 mg and isobaric bupivacaine TABLE 1. Characteristics of the Sample
FIGURE 1. Variation of visual analog scale (VAS) value from t0
to t . VAS of each patient was evaluated at different time points: before the implantation (t ), and at 3, 6, 12, 18, 24, 36, and 48 months after implantation (t –t ). At each time point, the mean and the standard deviation of VAS were computed. There was asignificant VAS reduction at t , t , t , and t (*p < 0.01).
Our initial study sample was 34 patients; however, because
of infections, two patients (5.8% of the sample) dropped
out of the study. Our final sample for analysis was 32
patients (10 men and 22 women) (Table 1). Our results
for mean values and standard deviations of VAS pain and
morphine and bupivacaine doses are reported in Table 2
and Figs 1– 3.
Pain ReliefThe initial VAS intensity of pain for each patient wasassessed before implantation at time 0 (t ). The mean VAS value at t was 8.01 ± 1.25 and after three months of IT therapy, at time 1 (t ), the mean value for VAS had decreased to 3.21 ± 2.04, a reduction in pain intensity of FIGURE 2. Variation of morphine dosage from t to t . Morphine
60%. There were no significant changes in the VAS until dosage (mg/day) of each patient was evaluated at different time 18 months after initiating therapy at t0 when it reached a points: before the implantation (t ), and at 3, 6, 12, 18, 24, 36, and mean value of 2.47 ± 1.54. Further decreases in the VAS 48 months after implantation (t –t ). At each time point, the mean and standard deviation of morphine dosage (mg/day) were computed.
were observed after 36 months (t ), VAS t = 1.96 ± 1.25 A significant increase in morphine dosage was appreciable at time and 48 months (t ), VAS, t = 1.28 ± 0.63, representing a points t , t , t , and t (*p < 0.05).
reduction in pain intensity of 85% from t (Table 2 and therapy, the dose had increased to 1.03 ± 0.61 mg/day.
The average morphine dose administered to patients These figures at t and t correlated well with the decrease before implantation at t was 0.41 ± 0.28 mg/day. After seen in the VAS as described in Table 2 and Fig. 2. The a slight increase at three months (t ) of IT therapy number of patients receiving morphine alone decreased (0.51 ± 0.33 mg/day), the mean morphine dose remained progressively over time from 23 at t to 11 at t (Table 3).
constant for up to 36 months (t ) when the mean dose Twelve patients had shifted from morphine alone to had reached 0.89 ± 0.57 mg/day. At t , at 48 months of TABLE 2. Visual Analog Scale (VAS) Score and the Dose of IT Drugs (Morphine and Bupivacaine) From t to t (Respectively Before the
Implantation and at 3, 6, 12, 18, 24, 36, and 48 Months After Implantation) TABLE 4. Types of Side-Effects
FIGURE 3. Variation of bupivacaine dosage from t to t .
Bupivacaine dosage (mg/day) of each patient was evaluated at different time points: before the implantation (t ), and at 3, 6, 12, 18, 24, 36, and 48 months after implantation (t –t ). At each time point, the mean and standard deviation of bupivacaine dosage(mg/day) of patients receiving bupivicaine and morphine IT werecomputed.
TABLE 5. Incidence of Side-Effects
TABLE 3. Number of Patients Receiving Morphine and Bupivacaine
or Morphine Alone for the Infusion IT Therapy at Each Time Point (From t to t : Before the Implantation and at 48 Months After Implantation, Respectively) quence of refilling his IDDS. This patient required urgent removal of the entire implanted system and was excluded from our study and data collection. Another patient had a constant slight increase in body temperature without centraleffects for 12 months after implantation that correlatedwith the presence of fluid in the pocket around the pump and for this reason the IT catheter and IDDS removed.
The number of patients requiring the addition of bupi- This patient also was excluded from the study.
vicaine to morphine varied during the different follow-up Side-effects of the drugs infused were experienced by 16 periods (Table 3). At t , nine patients required the out of 32 patients (50%) (Table 4). Only one side-effect addition of bupivacaine. At t , 19 patients required an was reported in 9.5% of patients, while the remaining addition of bupivacaine to improve analgesia and at t , patients had two or more side-effects (Table 5). The most 48 months after implantation, 21 patients required an frequent side-effect of IT therapy was constipation (34.4%), addition of bupivacaine. At the end of the study (t ), 35% followed by nausea (21.9%) and drowsiness (21.9%), of the total sample (32 patients) received only morphine, urinary retention (18.8%), itching (15.6%), vomiting whereas 65% of them required the addition of bupivicaine (12.5%), dizziness (12.5%), loss of appetite (12.5%), diarrhea (3.1%), xerostomia (3.1%), and impotence The average dose of bupivicaine did not vary significantly (3.1%). There were no side-effects that could be directly during follow-up periods, starting at 0.66 ± 0.12 mg/day at correlated to the use of bupivicaine, such as hypotension t and reaching a maximum mean value of 1.15 ± 0.58 mg/ day, 48 months (t ) after implantation (Fig. 3).
Recently, several studies regarding the use of IT infusion Complications were observed in two patients out of the 34 therapy have been published (15 –18). This suggests that enrolled. One patient had septic meningitis as a conse- long-term IT infusions of opioids are increasingly used as pain treatment for patients with noncancer pain (19). The therapy with an average morphine dose of 1.9 ± 1.9 mg/day main advantage of this technique is the considerable pain (range: 0.4 – 7.2 mg/day). Geriatric patients (72.3 ± 11.6 years) reduction (assessed as VAS score) that can be attainable enrolled in our study attained similar benefits with with IT infusions of analgesic medications (14 –16,20).
low-dose morphine, 0.89 ± 0.57 and 1.03 ± 0.61 mg/day The efficacy of IT administration of opioids for untreatable after 36 (t ) and 48 (t ) months of therapy, respectively.
pain is well documented in the literature (7,14 –17,21,22).
These results suggest that elderly patients have high Guidelines for dosing adjustments, IT drug trials, and sensitivity to IT opioid administration. It is our contention management of drug-related side-effects and symptoms that the dose of IT drugs for pain control in elderly popula- have also reported (7,23). Several authors report the use tions should be low at the initiation of therapy, and if an high dosages of drugs for IT therapy for the treatment of adjustment is needed, that adjustment should be made pain in nongeriatric patients (14,16,17,24 – 26). For example, slowly to avoid undesired side-effects.
Roberts and colleagues studied 80 patients with noncancer The reported incidence of complications following IT pain in a population of patients with an average age of therapy is significant; various technical complications such 53.4 years and reported that their average morphine dose as movement or malfunctioning of the catheter and lead was 9.95 ± 1.49 and 15.26 ± 2.52 mg/day after six and twisting, leading to suspension of therapy in 3.1% of cases, 36 months of IT therapy, respectively (17). Tutak and have been reported after implant (range: 37 – 2.7%) and Doleys assessed 26 patients (average age 44.3 years) with long-term follow-up studies (range: 8.7 – 7.2%) (25).
noncancer chronic pain and reported that their average Other authors, such as Anderson and Burchiel, have morphine dose was 1.38 and 9.34 mg/day after three and reported an device related complication incidence of 20% 21 months of IT therapy, respectively (20).
The purpose of our study was to investigate whether a Our study showed that IT therapy in this population of geriatric population of patients require lower doses of IT patients is safe. Indeed, only two patients of 34 enrolled analgesic drugs when compared to those doses required (5.88%) had serious complications requiring cessation of by less elderly populations (14). In our study, a VAS reduc- therapy. Moreover, and more significant, 16 out of 32 tion of 60% was achieved in a geriatric population at patients that finished the study (50%) experienced no three months of therapy and maintained over time. There side-effects. The 16 patients who did experience side- was a reduction of the mean VAS from 8.01 ± 1.25 to effects usually had more than one side-effect at any one 3.21 ± 2.04 after three months and to 1.28 ± 0.63 after time and none was serious; only 3 out of 16 (9.5%) 48 months of IT therapy (85% reduction). The morphine reported only one side-effect (Table 5).
dose required to provide adequate analgesia in this The most common side-effects reported were constipa- population of patients did not change significantly for up tion (34.4% of all patients) followed by nausea and to 36 months, suggesting that the analgesic effect of drowsiness (21.9%) and then urine retention (18.8%).
morphine remained constant. The increase in morphine Less reported side-effects included pruritis (15.6%), dose needed and observed at 36 and 48 months (0.89 ± 0.57 vomiting (12.5%), dizziness (12.5%), loss of appetite and 1.03 ± 0.61 mg/day, respectively), resulted in a signi- (12.5%), diarrhea (3.1%), xerostomia (3.1%), bradypnea ficant decrease in the VAS (Table 2 and Fig. 2) that could and respiratory depression (3.1%), and impotence (3.1%) be correlated to the onset of a low level of tolerance.
(Table 4). Interestingly to us, no patients reported direct Morphine alone sufficed for 35% our patients for the sequelae of their local anesthetic therapy such as paresthe- entire study period, whereas 65% of our study patients siae, paresis, gait impairment, orthostatic hypotension, needed the addition of bupivicaine at different stages of etc., as it has previously been shown (8).
the study to provide adequate analgesia. In order to In our study, 16 out of 32 (50%) patients reported provide improved pain control while keeping the doses of side-effects and 13 (81.3%) of them had two or more morphine stable, bupivicaine was added to morphine for side-effects, a relatively high incidence, even at low doses.
patients who reported a VAS = 4 at follow-up visits. At the Similar results have been reported by other authors same time, bupivicaine dosages were maintained at low (15,21,22). Elderly patients may be more sensitive to IT morphine or side-effects may be person related and not Our study, when compared to the studies in younger dose related. Further studies are suggested to address this patients of Roberts (17) and Tutak and Doleys (20), showed issue as to why elderly patients, at low doses of IT agents that elderly patients need lower doses of IT morphine have relatively high incidence of reported side-effects.
when compared to younger populations for pain control.
Moreover, Franco Gay (22) studied 39 patients with non- Conclusions
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