Long-term Intrathecal Administration Research Articles

Reversible Methotrexate‐Induced Dementia: A Case Report

Reversible Methotrexate‐Induced Dementia: A Case Report

Intrathecal Drug Administration in Chronic Pain Syndromes

Chronic pain may recur after initial response to strong opioids in both patients with cancer and patients without cancer or therapy may be complicated by intolerable side effects. When minimally invasive interventional pain management techniques also fail to provide satisfactory pain relief, continuous intrathecal analgesic administration may be considered. Only 3 products have been officially approved for long-term intrathecal administration: morphine, baclofen, and ziconotide. The efficacy of intrathecal ziconotide for the management of patients with severe chronic refractory noncancer pain was illustrated in 3 placebo-controlled trials. A randomized study showed this treatment option to be effective over a short follow-up period for patients with pain due to cancer or AIDS. The efficacy of intrathecal opioid administration for the management of chronic noncancer pain is mainly derived from prospective and retrospective noncontrolled trials. The effect of intrathecal morphine administration in patients with pain due to cancer was compared with oral or transdermal treatment in a randomized controlled trial, which found better pain control and fewer side effects with intrathecal opioids. Other evidence is derived from cohort studies. Side effects of chronic intrathecal therapy may either be technical (catheter or pump malfunction) or biological (infection). The most troublesome complication is, however, the possibility of granuloma formation at the catheter tip that may induce neurological damage. Given limited studies, the evidence for intrathecal drug administration in patients suffering from cancer-related pain is more compelling than that of chronic noncancer pain.

A Case of Cancer Pain Management by Long-Term Intrathecal PCA

Titration of oral or intravenous medication is the preferred method of pain management for most patients with cancer pain. However, some patients experience insufficient pain relief or considerable adverse effects from systemic opioids. For these reasons, the control of severe cancer pain continues to present a variety of challenges to clinicians. We report our experience of successfully managing cancer pain in a patient by means of long-term intrathecal administration of morphine, bupivacaine, and racemic ketamine via a patient-controlled delivery system. This therapy reduced the patient's nausea, vomiting, and somnolence, led to early hospital discharge, and increased her level of daily activity. There were no signs of motor paralysis, psychomimetic alteration, neurological dysfunction, or infection related to the intrathecal route during treatment. Intrathecal therapy is an effective treatment in terminally ill patients.

Long-term intrathecal morphine influence on major compounds of the endocrine system in elderly population

Background The influence of long-term opioid administration on hormonal levels is not well characterized in the literature. We previously showed that intrathecal opioid therapy significantly influences the homeostasis of immune and endocrine systems. Other authors confirmed that exogenous and endogenous opioids induce this effect. They have a cytokine-like behavior and may function as neurotransmitters, neuromodulators or hormones, as concerning their synthesis, storage and release. Aims To assess the effects of morphine long-term intrathecal administration on serum levels of Gonadal, Thyroidal and Adrenal axis hormones in an elderly population affected by chronic pain; to assess the correlation between hormone levels and morphine dosage. Methods Patients suffering from chronic non-cancer pain with or without intrathecal drug delivery system were studied and hormonal levels were monitored, using an immunoradiometric assay kit. Results The long-term administration of intrathecal morphine influenced part of the endocrine system, in particular, there was a reduction of FSH and LH and an increment of GH serum levels; this effect was morphine dose dependent. Conclusion Long-term intrathecal opioid administration influenced FSH, LH and GH serum levels. Data on this issue are inadequately described in the literature. The finding of endocrine effects of opioid therapy, nonetheless, cannot be ignored, as it may have clinical relevance in both elderly and young population. We believe that during long intrathecal pain treatments with morphine, clinicians should be aware of both immediate and later opioids side effects, and in particular, they should monitor immune and endocrine changes.

Stability of a Baclofen and Clonidine Hydrochloride Admixture for Intrathecal Administration

Implantable infusion pumps for the intrathecal administration of analgesics are commonly used in the treatment of severe or intractable chronic pain. Drugs used in these pumps include morphine, baclofen, clonidine, hydromorphone, meperidine, fentanyl, and bupiva-caine. This study investigates the chemical and physical stability of baclofen (1000 mcg/mL) and clonidine hydrochloride (200 mcg/mL) at 37°C for 10 weeks using a stability-indicating HPLC assay. The formulations included baclofen alone, clonidine hydrochloride alone, and a mixture of the two drugs. At each time point, the amount of drug remaining was greater than 90% of original. Week 10 percentages were 99.7% for baclofen alone, 100.7% for clonidine alone, and 103.2% and 101.1% for baclofen and clonidine hydrochloride, respectively in the drug mixture. These results demonstrate the stability of this admixture for long-term intrathecal administration.

Endocrine consequences of long-term intrathecal administration of opioids.

Intrathecal administration of opioids is a very efficient tool in the long-term control of intractable nonmalignant pain. However, despite the well known role of opioids in endocrine regulation, few data are available about possible effects on hypothalamic-pituitary function during this treatment. Seventy-three patients (29 men and 44 women; mean age, 49.2 +/- 11.7 yr) receiving opioids intrathecally for nonmalignant pain were enrolled for extensive endocrine investigation. At the time of hormonal determination, the mean duration of opioid treatment was 26.6 +/- 16.3 months; the mean daily dose of morphine was 4.8 +/- 3.2 mg. The control group consisted of 20 patients (11 men and 9 women; mean age, 54.2 +/- 14.0 yr) with a comparable pain syndrome but not treated with opioids. Decreased libido or impotency was present in 23 of 24 men receiving opioids. The serum testosterone level was below 9 nmol/L in 25 of 29 men and was significantly lower than that in the control group (P < 0.001). The free androgen index was below normal in 18 of 29 men and was significantly lower than that in the control group (P < 0.001). The serum LH level was less than 2 U/L in 20 of 29 men and was significantly lower than that in the control group (P < 0.001). Serum FSH was comparable in both groups. Decreased libido was present in 22 of 32 women receiving opioids. All 21 premenopausal females developed either amenorrhea or an irregular menstrual cycle, with ovulation in only 1. Serum LH, estradiol, and progesterone levels were lower in the opioid group. In all 18 postmenopausal females significantly decreased serum LH (P < 0.001) and FSH (P = 0.012) levels were found. The 24-h urinary free cortisol excretion was below 20 microg/day in 14 of 71 opioid patients and was significantly lower than that in the control group (P = 0.003). The peak cortisol response to insulin-induced hypoglycemia was below 180 microg/L in 9 of 61 opioid patients and was significantly lower than that in the nonopioid group (P = 0.002). The insulin-like growth factor I SD score was below -2 SD in 12 of 73 opioid patients and was significantly lower than that in the control group (P = 0.002). The peak GH response to hypoglycemia was below 3 microg/L in 9 of 62 subjects and was significantly lower than that in the control group (P = 0.010). Thyroid function tests and PRL levels were considered normal. No metabolic disturbances were recorded, apart from significantly decreased high density lipoprotein cholesterol levels (P = 0.041) and elevated total/high density lipoprotein cholesterol ratio (P = 0.008) in the opioid group compared to the control group. Supplementation with gonadal steroids improved sexual function in most patients. In conclusion, of all patients receiving intrathecal opioids, the large majority of men and all women developed hypogonadotropic hypogonadism, about 15% developed central hypocorticism, and about 15% developed GH deficiency. These findings suggest that further investigations are required to determine the need for systematic endocrine work-up in these patients and the necessity for substitutive therapy.

Endocrine Consequences of Long-Term Intrathecal Administration of Opioids

Endocrine Consequences of Long-Term Intrathecal Administration of Opioids

Long-term intrathecal administration of glycine prevents mechanical hyperalgesia in a rat model of neuropathic pain

Neuropathic pain has been postulated to be mediated, in part, by amino acid neurotransmitters including glycine. The current study examined the effects of continuous intrathecal glycine administration (0.1 µmol 0.5 µl-1 h-7 on the development of mechanical hyperalgesia and other features of neuropathic pain evoked by unilateral loose ligation of the sciatic nerve in the rat Each hind paw was tested for withdrawal threshold to mechanical stimuli prior to, and after ligation at intervals of 3, 6, 9, 12 and 16 days. Pain behavior (posture and gait) and hind paw dystrophic features (redness and swelling) were also examined. Glycine increased the normal mechano-nociceptive responses and prevented the development of mechano-nociceptive hyperalgesia. Spontaneous nociceptive behavior and hind paw dystrophic features, seen in the saline treated rats, were significantly diminished. Our results suggest that spinal cord inhibitory glycinergic activity is important for normal mechano-receptive responsitivity and development of mechano-nociceptive hyperalgesia in this model. [Neurol Res 2000; 22: 160-1 64]

Chronic Intrathecal Administration of Dexamethasone Sodium Phosphate: Pharmacokinetics and Neurotoxicity in an Animal Model

Although corticosteroids have been used intraspinally for many years, long-term intrathecal administration has not been examined. We have assessed the stability, bioavailability, and safety of continuously delivering the prodrug dexamethasone sodium phosphate into the lumbar subarachnoid space. High-performance liquid chromatography studies were performed to determine whether dexamethasone sodium phosphate is degraded either in vials or in an infusion pump at 37 degrees C during a period of weeks. Rats then received implants with a combined intrathecal delivery and microdialysis sampling catheter to determine whether the prodrug is converted to free dexamethasone. A neurotoxicity study was performed in which rats received implants with an intrathecal catheter and were continuously infused with the corticosteroid during a 2-week period. Dexamethasone sodium phosphate, diluted in saline, is stable at body temperature in vials and implantable infusion pumps for at least 2 weeks. When delivered into the cerebrospinal fluid as a bolus, virtually all of the prodrug is converted to free dexamethasone within 40 minutes. When administered continuously, most of the corticosteroid is in its active form at steady state. Low doses of corticosteroid (< or =12.5 ng/h) produced no side effects or neuropathology in the rats, but a higher dose (125 ng/h) was associated with inflammation in the lumbar subarachnoid space. Dexamethasone sodium phosphate is a stable prodrug that is efficiently converted to free dexamethasone when delivered intrathecally. Low continuous intrathecal doses seem safe, but higher doses may lead to increased inflammation.

Long-Term Intrathecal (IT) Administration of Opioid and Bupivacaine Relieved Intractable Pain in a Patient with Familial Amyloidosis Polyneuropathy: A Case Report

Introduction. At the present time, there is no reliable method or drug for effective relief of the severe pain caused by the amyloldotic polyneuropathy (AP). Objective. To explore the possibility of relieving this type of pain by intrathecal (IT) infusion of opioid (morphine or buprenorphine), with or without bupivacaine. Patients, Materials and Methods. A 49-year-old male AP patient with Intractable pain in the low back, lower abdomen, and lower extremities. Opioids (up to 20 mg parenteral morphine-eq/day), and epidural injections of morphine (up to 36 mg/day) failed to provide long-term satisfactory pain relief. Therefore, an IT catheter was inserted via the L3-L4 interspace with its tip located at the L1-L2 intervertebral disk. Results. Intermittent IT injections of morphine from 5 to 30 mg per day, for 124 days, and continuous IT infusion of morphine (2-4 mg/ml), combined with bupivacaine (1.0-2.0 mg/ml), in daily rates from 2 to 12 ml (median = 9.5) for another 67 days, were associated with occurrence of seizures, suspected to be caused by the IT morphine. Therefore, the IT morphine was replaced with IT buprenorphine. Thereafter, the pain was treated with IT infusion of buprenorphine (0.06 mg/ml) and bupivacaine (1.25 mg/ml) in daily rates from 4 to 13 ml (median = 5) for another 676 days, until the patient's death, for reasons unrelated to the IT treatment. He experienced satisfactory pain relief with daily doses of IT opioid from 4.5 to 39 mg morphine-eq (median = 19.6 mg) and IT bupivacaine from 0 to 20 (median = 12.5). The mean visual Analog Scores (VASmean), decreased from 7 to 0 (out of 10), the gait improved; and nocturnal sleep increased from 1 to 7-8 hours. Respiratory insufficiency (attributed to an an IT daily dose of ∼ 5 mg morphine) and orthostatic hypotension, pareses, and urinary retention occurring at low doses of (12-18 mg/day) of IT bupivacaine were recorded. The patient had the IT treatment for 867 days, of which 777 days (> 90%) were spent at home. Conclusion. Long-term IT administration of opioid and bupivacaine provided satisfactory long-term pain relief in a patient with refractory pain due to AP.