Lennart Appelgren

Complications of Intrathecal Opioids and Bupivacaine in the Treatment of “refractory” Cancer Pain

ObjectiveTo test the concept that externalized tunneled intrathecal catheters lead to a high risk of complications, such as meninigitis and epidural abscess, and therefore should not be used for durations of intrathecal pain treatment of > 1 week. DesignProspective, cohort, nonrandomized, consecutive, historical control trial. SettingTertiary care center, institutional practice, hospitalized and ambulatory care. PatientsTwo hundred adults (107 women, 93 men) with refactory cancer pain treated for 1–575 (median, 33; total, 14,485) days; 79 patients were treated at home for 2–226 (median, 36; total, 4, 711) days. All patients had died by the close of the study. InterventionsInsertion of intrathecal tunneled nylon (Portex) catheters (223 in 200 patients) with Millipore filters. The catheter hubs were securely fixed to the skin with steel sutures. Standardized care after insertion: (a) daily phone contact with the patients, their families, or the nurses in charge; (b) weekly dressing change at the tunnel outlet by the nurses; (c) refilling of the infusion containers by the nurses; (d) exchange of the infusion systems when empty (within 1 month) and of the antibacterial filter once a month by specially instructed Pain Department nurses. All contact between the connections of the syringes, cassettes, and needles with the operators hands was carefully avoided during filling and refilling of the infusion containers and exchange of the antibacterial filters; no other aseptic precautions were taken. Main Outcome MeasuresWe recorded the rates of perfect function and complications of the systems. The rates of complications recorded in this study with externalized tunneled intrathecal catheters are discussed and compared with the rates reported in the literature with externalized (tunneled and nontunneled) epidural and intrathecal catheters, as well as with internalized (both epidural and intrathecal catheters connected to subcutaneous ports, reservoirs, and pumps. ResultsThe following rates (as a percentage of number of patients) of perfect function and complications of the systems were recorded (the ranges of rates reported in the literature are given in parentheses): perfect function of the system, 93% (31–90%); accidental injury of an unknown epidural tumor followed by an epidural hematoma, 0.5% (04%); skin breakdown at the insertion site, 2% (2–50%); postdural puncture headache, 15.5% (10%); external leakage of CSF, 3.5% (427%); CSF hygroma (“pseudomeningocele”), 1.5% (4− 6.25%); hearing loss and MBniBre-like syndrome, 0% (12%); pain on injection, 0% with continuous infusion and 4.5% with intermittent injections (3–36% with intermittent injections); catheter tip dislodgement, 1.5% (633%); catheter (system) occlusion, 1% (3–12%); accidental catheter withdrawal, 4% (3–22%); catheter (system) leakage, 1.5% (2.1–26.6%); all mechanical complications, 8.5% (1044%); local (catheter entry site) infection, 0.5% (2–33%); catheter track infection, 0% (625%); epidural abscess, 0% (0.625%); meningitis, 0.5% (1–25%); systemic infection, 0% (3%); incidence of all infections (nhreatment days), 1 /7,242 ( 1 / 168− 1 /2,446). ConclusionsIn our population and with the technique of insertion and care reported here, the use of externalized tunneled intrathecal catheters has not been associated with higher rates of complications when compared with earlier reported rates of externalized epidural catheters and internalized (both epidu- ral and intrathecal) catheters connected to subcutaneously implanted ports, reservoirs, and pumps. The opinion that the use of externalized tunneled in- trathecal catheters should be restricted only to patients who need pain treat- ment for <1 week (because of the potential risk of infection, particularly men- ingitis and epidural abscess) is unfounded.

Long-term intrathecal morphine and bupivacaine in “refractory” cancer pain. I. Results from the first series of 52 patients

Neither epidural (EDA) or intrathecal (IT) morphine nor EDA opiate + bupivacaine provides acceptable relief of some types of cancer pain, e. g. pain originating from mucocutaneous ulcers, deafferentation pain, continuous and intermittent visceral and ischaemic pain, and that occurring with body movement as a result of a fracture. To improve pain relief in such conditions, we gave combinations of morphine and bupivacaine through open IT‐catheters to 52 patients with “refractory”, severe (VAS 7–10 out of 10), complex cancer pain (Edmonton Stage‐3), for periods of 1–305 (median = 23) days. The efficacy of the treatment was estimated from: 1) daily dosage (intraspinal and total opiates, and intraspinal bupivacaine), and 2) scores of non‐opiate analgesic and sedative consumption, gait and daily activities, and amount and pattern of sleep. Forty‐four patients obtained continuous and acceptable pain relief (VAS 0–2), 26 of them with daily doses of IT‐bupivacaine of <30 mg/day (<1. 5 mg/h). Higher IT‐bupivacaine doses (>60–305 mg/day), not always giving acceptable pain relief, were necessary in 13 patients with deafferentation pain from the spinal cord or brachial or lumbosacral plexuses or pain from the coeliac plexus, or from large, ulcerated mucocutaneous tumours. By combining IT‐bupivacaine with IT‐morphine, it was possible to use relatively low IT‐morphine doses (10–25 mg/day during the first 2 months of treatment) in more than half of the patients. The IT‐treatment significantly decreased the total (all routes) opiate consumption and significandy improved sleep, gait and daily activities. For the whole period of observation (6 months), the IT‐treatment was assessed as adequate in 3. 8%, good in 23. 1%, very good in 59. 6% and excellent in 13. 5% of the cases. Adverse effects of the IT‐bupivacaine (paraesthesiae, paresis, gait impairment, urinary retention, anal sphincter disturbances and orthostatic hypotension) did not occur with doses of 2. 5–3. 0 mg/h (approx. 60–70 mg/day).

Long-term Intrathecal Morphine and Bupivacaine in Patients with Refractory Cancer Pain Results from a Morphine, Bupivacaine Dose Regimen of 0.5:4.75 mg/ml

BackgroundThere are no clinical data regarding the ratios and concentrations in which morphine and bupivacaine should be combined, when given intrathecally, to improve analgesia while decreasing adverse effects. This study was undertaken to test the clinical efficacy of a constant infusion of 0.5 mg/ml morphine plus 4.75 mg/ml bupivacaine (morphine: bupivacaine ≈1:10), given through open intrathecal catheters. MethodsIn 53 patients, the clinical efficacy was estimated from: pain relief (visual analog scale scores 0–10); daily dosages (intrathecal and total opioid and intrathecal bupivacaine); scores (0–5) of nonopioid analgesic and sedative consumption, gait and daily activity, and amount of sleep; and rates of adverse effects. ResultsDuring the intrathecal period (7–334, median 29 days), all 53 patients obtained acceptable pain relief (visual analog scale scores 0–2 vs. 6–10 in the pre-intrathecal stage). The total opioid daily consumption decreased (median 10 vs. 120 mg), the sleep was about two times longer, the nonopioid analgesic and sedative consumption about two times lower, and the gait ability pattern was unchanged. The daily dose of intrathecal morphine (median 6 mg) and the daily intrathecal volumes (median 10 ml) were low, whereas the daily dose of intrathecal bupivacaine was relatively high (median 50 mg). Side effects potentially related to intrathecal morphine (seizures, cerebral, and spinal clonus) were not recorded. Side effects attributable to intrathecal bupivacaine (in patients not having these complications before the intrathecal treatment) occurred in the forms of late urinary retention (9 of 27), paresthesias (11 of 27), paresis/gait impairment (9 of 27), and occasional episodes of orthostatic arterial hypotension (1 of 53 patients). ConclusionsA constant intrathecal infusion with a morphine:bupivacaine ratio of = 1:10 and concentrations of morphine of 0.5 mg/ml and bupivacaine of 4.75 mg/ml may significantly improve the relief of refractory cancer pain with a certain risk of adverse effects (which should be balanced against pain by the patient) from the relatively high intrathecal bupivacaine doses and concentration.

Epidural versus intrathecal morphine-bupivacaine: Assessment of consecutive treatments in advanced cancer pain

Twenty-five patients with multifocal and multitype (somatic, visceral, and neurogenic) advanced cancer pain who experienced severe pain despite extradural (ED) morphine and bupivacaine were converted to intrathecal (IT) morphine and bupivacaine. The consecutive ED and IT periods (2-174 days, median = 50 days, and 1-305 days, median = 37 days, respectively) were assessed in clinical terms (daily analgesic dosages giving acceptable pain relief and quality of life expressed as sleeping hours and walking/daily activities). With the IT treatment, the total (all routes) opiate consumption and the daily doses of spinal morphine and spinal bupivacaine decreased significantly at the beginning of the treatment compared to the ED period, and continued to be significantly reduced for up to 1 wk for spinal opiate and bupivacaine and 6 mo for total opiate. The spinal opiate and bupivacaine doses were still lower in 50% of the patients at the end of the IT treatment compared to the end of the ED period. When final ED versus initial (2nd day) IT doses were assessed, the daily median dose ratios were 7.5 for total opiate and 4 for both spinal opiate and bupivacaine. Subsequently, lower daily volumes and higher concentrations were needed for IT administration of the drugs. During the first month of the IT treatment, sleeping and walking scores improved compared to ED treatment. Thus, the IT treatment gave more satisfactory pain relief, and--because of lower daily doses and volume--proved to be more suitable for treatment at home (continuous infusion from external pumps) than the ED treatment.

Bacteriology, drug stability and exchange of percutaneous delivery systems and antibacterial filters in long-term intrathecal infusion of opioid drugs and bupivacaine in refractory' pain

ObjectiveTo provide a basis for recommendations on the exchange of containers (syringes and cassettes) and antibacterial filters, and for choice of administration device in patients with “refractory” pain treated with long-term percutaneous intrathecal (IT) infusions of opioid (morphine or buprenorphine) and bupivacaine mixtures. DesignProspective, cohort, nonrandomized control trial-case series, with consecutive sample, no standard criterion, and cost-benefit analysis. SettingTertiary care center, institutional practice as well as hospitalized and ambulatory care. PatientsEighty-nine (51 women and 38 men); 81 with malignant pain and 8 with benign “refractory” pain. Interventions(a) The chemical stability of the drugs in the containers during 30 days, (b) The results of bacteriologic culture of the residual volumes of the analgesic mixtures from used and reused (1–16 times) syringes (n = 135) and cassettes (n = 258), and of 5 ml of sterile isotonic saline filtered through the used Millipore filters (n = 149). The bacteriologic samples from the 89 patients were taken after 1–40 (median = 7), 1–86 (median = 20), and 5–78 (median =31) days of IT treatment, respectively. Main Outcome MeasuresChemical stability: buprenorphine and bupivacaine concentrations-liquid chromatography; morphine concentrations-gas chromatography. Bacteriologic cultures: standard laboratory procedures. The hypothesis (repeated use of the infusion systems and their exchange once a month does not significantly affect drug concentrations or increase the infection risk) was elaborated before data collection began. ResultsThe bupivacaine-opioid mixtures were found to be chemically stable within 3–10% of the original doses up to 30 days. Seventeen cultures (from five syringes, six cassettes, and six filters) in 13 patients (having no signs of meningeal infection) were found to be colonized with Staphylococcus.

Continuous Intracisternal and High Cervical Intrathecal Bupivacaine Analgesia in Refractory Head and Neck Pain

Background The upper cervical component of the spinomesencephalic tract and cranial nerves V, VII (nervus intermedius), IX, and X are involved in mechanisms of acute and chronic pain from head and neck structures. To date there is no reliable method for relief of refractory pain (i.e., pain that cannot be relieved by conventional pharmacologic therapies) from these structures. Therefore, we explored continuous intracisternal infusion of bupivacaine for the treatment of refractory pain of the head and neck. Methods Intracisternal catheters were inserted in 13 adults with refractory nonmalignant (n = 4) and malignant (n = 9) pain from the head, face, mouth, neck, and upper extremities; 0.5% plain bupivacaine was infused continuously at rates of 1-7 (median 1.5) mg/h with optional bolus doses of 0.5-2.0 mg 4-2 times/h. The efficacy was assessed from pain relief (daily VASmax, VASmin, and VASmean scores 0-10), daily doses of intracisternal bupivacaine and total opioid (expressed as mg parenteral morphine-eq), amount of nocturnal sleep, and rates of adverse effects. Results The 13 patients were treated for 3-182 days (median 37, total 712 days), 3 patients being treated at home for 10-112 days (median 88, total 210 days). In one patient, the efficacy of the treatment could not be estimated because of advanced senility. Eleven of the remaining 12 patients obtained acceptable pain relief with daily doses of intracisternal bupivacaine ranging from 20 to 118 mg (median 37 mg): VAS sub mean scores decreased from 7 to 2, mean pain relief increased from 30% to 80%, total opioid daily dose decreased from 53 to 36 mg parenteral morphine-eq, and nocturnal sleep increased from 2 to > 6 h (all figures are median values). Speech, eating, walking, and natural functions were generally not affected. Side effects such as tiredness and malaise, somnolence and sleep, feeling of coldness in the neck and skull base, transient post-spinal puncture headache, paresthesias, hoarseness, dysphagia, transient paresis of the upper/lower extremities, episodic miosis and conjunctival hyperemia, and transient orthostatic arterial hypotension were each observed in one or two patients. No patient presented clinical evidence of phrenic nerve paralysis. There was no nausea or vomiting. No persistent neurologic deficit or death could be attributed to the intracisternal pain treatment. Conclusions Continuous intracisternal infusion of bupivacaine may be a useful method in exceptional, well selected patients with refractory pain from the head and neck structures. Further studies are necessary to establish the indications and the safety of the method.

High thoracic/low cervical, long‐term intrathecal (IT) infusion of bupivacaine alleviates “refractory” pain in patients with unstable angina pectoris: Report of 2 cases

Background: There is no reliable treatment for “refractory” pain from unstable angina pectoris (UAP) when epidural infusion of bupivacaine has failed to relieve it. In two such cases we explored the potential of intrathecal (IT) bupivacaine infusion to provide pain relief.

Penetration forces in cannulation of the dorsal veins of the hand: I. A comparison between polyurethane (Insyte®) and polytetrafluoroethylene (Venflon®) cannulae

The functional tip tapering design of peripheral venous cannulae (introducer steel needle + catheter) made of polyurethane (PUR‐Insyte®) and polytetrafluoroethylene (PTFE‐Venflon®) was studied with 3 techniques: A) Scanning electron microscopy (SEM). B) Measurement of penetration forces in vitro through latex membranes and lamb skins with a tensile‐compression apparatus (Instron‐1122®) at 1) the introducer steel‐needle point, 2) the needle heel (the spot marking the passage from the point of the needle to its shaft), 3) the catheter top (i.e. the beginning of the plastic sheath), 4) the catheter tip, i.e. the beginning of the largest diameter of the plastic sheath, and 5) between the catheter tip and its hub (catheter friction). C) Two cannulae (one of each type for every subject) were inserted at random into the dorsal veins of the left and right hand in 37 volunteers, and the penetration forces were measured with a force transducer. Results: A) The PUR‐cannulae had a lancet‐like appearance and a smoother transition at the catheter top, whilst the PTFE cannulae were arrow‐like, cut back and had a less accentuated conical design. B) Penetration forces in vitro through latex membranes were 9–41 times lower (P<0.0001) than those through the lamb skins. The highest forces (mean · s.d.) registered in vitro (lamb skins) were 4.1 ± 0.2 Newtons (N) with PUR‐cannulae at the catheter tip, and 3.4 ± 0.6 with the PTFE‐cannulae at the catheter top (P<0.05). C). In in vivo (volunteers), significantly (P<0.001) higher forces were required with the PUR‐cannulae than with the PTFE‐cannulae for penetration of both the skin (3.9 ± 1.6 vs 2.7 ± 0.8 N) and the vein wall with continued penetration of the skin (3.5 ± 1.2 vs 2.4 ± 0.9 N). When the highest penetration forces were compared, no significant differences between in vitro (lamb skins) and in vivo (skin and vein with continued skin penetration) studies were found with either of the two cannulae studied. We conclude that there were statistically significant differences between penetration forces of the PUR and PTFE‐cannulae when inserted into the dorsal veins of the hand. Penetration forces in vitro (lamb skins) may predict with acceptable accuracy the penetration forces in vivo (dorsal veins of the hand).