Intrathecal Opioid Administration Research Articles

UP-01.90: Effect of lumbar-epidural administration of tramadol on neurophysiology of bladder

Intrathecal and epidural administration of μ-agonist opioids like morphine are associated with urinary retention which is a potentially serious adverse event. In animal studies, tramadol has been found not to affect voiding function. We evaluated the urodynamic effects of epidural tramadol in human subjects.

A history of neuraxial administration of local analgesics and opioids.

The history of intrathecal and epidural anaesthesia is in parallel with the development of general anaesthesia. As ether anaesthesia (1846) is considered the first modern anaesthetic since its use by Morton 157 yr ago, so Bier made history by using cocaine for intrathecal anaesthesia in 1898. The first published report on opioids for intrathecal anaesthesia belongs to a Romanian surgeon, Racoviceanu-Pitesti, who presented his experience at Paris in 1901. It was almost a century before the opioids were used for epidural analgesia. Behar and his colleagues published the first report on the epidural use of morphine for the treatment of pain in The Lancet in 1979. Epidural and intrathecal opioids are today part of a routine regimen for intra- and postoperative analgesia. Over the last 30 yr, the use of epidural opioids has became a standard for analgesia in labour and delivery, and for the management of chronic pain. Finally, epidural opioids have been shown to have a pre-emptive effect, when used before major surgery. We present the evolution of neuraxial anaesthesia and the history of intrathecal and epidural administration of opioids.

Efficacy and Safety of Epidural Opioids for Postoperative Analgesia

Epidural narcotic analgesia was assessed in 66 patients after surgery under epidural and light general anesthesia. Changes of forced expiratory volume in 1 s (FEV 1 ) were measured after upper abdominal or thoracic surgery in 41 patients, and comparisons were made with results in an additional 17 upper abdominal surgery patients who received general anesthesia and muscle relaxants followed by intravenous morphine for postoperative pain relief. Methadone, 1.0 mg, hydromorphone, 1.0 mg, or morphine sulfate, 5 mg, was administered epidurally and increments were repeated as necessary until satisfactory analgesia was reported, with the following results (mean ± SD): intravenous morphine: latency 3 to 10 min, duration 3.1 ± 1.6 h; epidural methadone: latency 17.2 ± 4 min, duration 5.6 ± 2.7 h; epidural hydromorphone: latency 22.5 ± 6 min, duration 9.8 ± 5.5 h; epidural morphine: latency 36 ± 6 min, duration 16.4 ± 7 h. Duration of action was slightly longer after lower abdominal surgery. Addition of epinephrine 1/200,000 to the epidural narcotic solutions did not prolong duration. Narcotic requirements for satisfactory analgesia were approximately the same by the intravenous route as by the epidural route and equivalent to 8.5 to 9 mg of morphine. FEV 1 was reduced to 36.8 ± 13.2% of preoperative control values after general anesthesia and muscle relaxants and to 46 ± 12% of control after epidural and general anesthesia. Intravenous morphine improved FEV 1 to 45.3 ± 12% of control, whereas epidural narcotics and local anesthetics produced a greater increase of FEV, in the following amounts: epidural local anesthetic to 68.7 ± 9.1% of control and epidural narcotics to 67.1 ± 14.7% of control. Epidural narcotics did not cause sympathetic depression or bladder dysfunction, and analgesia was segmental. We conclude that epidural narcotics in adequate dosage are an effective means for production of prolonged and segmental postoperative analgesia.

Subarachnoid Analgesia in Advanced Labor: A Comparison of Subarachnoid Analgesia and Pudendal Block in Advanced Labor: Analgesic Quality and Obstetric Outcome

Pain control during labor is a primary objective of antalgic therapy. The use of the peridural as an elective procedure for labor analgesia is now corroborated by the international scientific community. Sometimes a combined spinal-peridural procedure is used together with the intrathecal administration of opioids to also cover the first stage of labor. Unfortunately, patients and/or gynecologists often request analgesia in a late stage of labor. The aim of our study was to evaluate the possibility of using a subarachnoid block alone for labor analgesia when this is requested at a late stage, that is, in advanced labor with cervical dilation greater than 7 cm. After approval by our ethics committee and the written and informed consent of the patients, 111 women were enrolled in this study and randomly divided into two groups. The first group (Group S: 55 patients) received a subarachnoid block with 2.5 mg hyperbaric bupivacaine + 25 mug fentanyl + 1 mL 10% glucose. A pudendal nerve block with 7 mL 2% mepivacaine in each side was administered to the second group (Group P: 56 patients). In both groups, careful maternal-fetal monitoring was conducted, and pain was scored on a numerical scale from 0 to 4, 10 minutes after placement of the block (time [T] 0), at delivery (T1), and at episiorrhaphy (T2). In all patients, we recorded any side effects, the Apgar score at birth and after 5 minutes, the administration of other analgesic and/or sedative drugs, the degree of satisfaction, and the time of hospitalization after delivery. Evaluations were performed by anesthesiologists unaware of patients' treatment group. The duration of spinal analgesia was considered to be the time from injection of study drugs to the time of the patient's first request for additional analgesia. In no cases were there any side effects worthy of note, and hospitalization never exceeded 72 hours. The Apgar score was always between 7 and 10. All except one of the women in Group S were satisfied or more than satisfied with their pain management, whereas 50 women in Group P expressed only moderate satisfaction or dissatisfaction (P < 0.0001). In most patients in Group S, complete analgesia was obtained. In Group P, however, 10 minutes after placement of the pudendal nerve block, 40 patients reported no improvement in pain symptomatology during contractions and only 16 reported less painful contractions (P < 0.0001). The duration of spinal analgesia (128 +/- 38 minutes) was enough in most cases for delivery to be completed. These results suggest that low-dose bupivacaine-fentanyl spinal analgesia represents an important option for pain relief in late labor, not the least because the procedure does not upset the dynamics of delivery or alter vital parameters and is welcomed by women in labor who are still able to collaborate actively in the birth of their baby.

Recent insights into the pharmacokinetics of spinal opioids and the relevance to opioid selection

Spinal opioid administration was introduced into clinical practice nearly 25 years ago in the hope of producing intense spinal analgesia that was devoid of the dose-limiting side effects associated with systemic opioid administration. While spinal opioid administration can clearly be an effective analgesic technique, there is a widespread misconception that any opioid administered epidurally or intrathecally will produce analgesia by a selective spinal mechanism. This is simply not true; multiple opioids that are commonly administered spinally produce analgesia by uptake into the systemic circulation with subsequent redistribution to brainstem opioid receptors. In an effort to help clinicians understand why some opioids are not suitable for selective spinal analgesia, this review describes recent insights into the fate of intrathecally and epidurally administered opioids. A series of animal studies published over the last 4 or more years have provided the first measurements of opioid concentration in the epidural space, intrathecal space, spinal cord and peri-spinal tissues following intrathecal and epidural opioid administration. These studies characterize, for the first time, the factors governing the rate and extent to which different opioids redistribute from the epidural and intrathecal spaces to reach target opioid receptors in the spinal cord dorsal horn. The findings indicate that increasing lipid solubility decreases the spinal cord bioavailability of spinally administered opioids. These animal data help to explain multiple clinical studies that have demonstrated that the analgesic effect of spinally administered lipid-soluble opioids is due in part, if not exclusively, to uptake into plasma and distribution to brainstem opioid receptors.

Intrathecal Opioid Infusions

Despite the lack of large epidemiologic studies to date, increased reporting of the inflammatory mass phenomenon as a consequence of scientific presentations and “Dear Doctor” letters to physicians, as well as the availability of new preclinical data, motivated the organization of a consensus panel. This panel’s goal was to formulate hypotheses about the etiology of catheter-tip masses and to provide recommendations for clinicians about the detection and treatment of this complication.1,2Together, these papers provide a comprehensive review of the preclinical and clinical data available regarding the incidence, etiology, and clinical features of inflammatory masses associated with intrathecal drug infusion and provide recommendations for screening, detection, diagnosis, treatment, and prevention of these masses. These recommendations emphasize the need for physician awareness, attentive patient follow-up, and maintaining intrathecal opioid dose and concentration as low as possible for as long as possible while still achieving adequate analgesia.It remains that inadequately treated chronic pain is a serious condition that is associated with its own risks and morbidity. In that context, the risk of catheter-tip mass development as a consequence should remain acceptable provided the treatment is effective. The authors thank Drs. McMillan and Aldrete for their interest and their comments. We share Dr. McMillan’s view on the importance of defining the true incidence and risk of inflammatory mass formation. It is clear that the incidence of granuloma formation is underestimated because of the voluntary nature of reporting and the unknown incidence in asymptomatic patients. The authors believe, however, that imaging of all patients on intrathecal therapy for chronic pain is not supported by the current literature. Given the serious adverse impact of this complication and the likely increase in its incidence with long-term intrathecal opioid administration in noncancer pain populations, the authors believe that the same goals can be reached if physicians maintain a low threshold for ordering imaging studies in patients perceived to be at risk. Even subjective or relatively minor symptoms in a patient receiving long-term or high-dose intrathecal opioid therapy may justify an imaging study to rule out the possibility of a catheter-tip mass. Contrast-enhanced magnetic resonance imaging is the imaging modality of choice, although computed tomography–myelography is less costly and also effective in confirming the diagnosis.* The University of Texas M.D. Anderson Cancer Center, Houston, Texas. samuel@neosoft.com

Epidural Analgesia for Childbirth

New low-dose, local anesthetic-opioid combinations, combined spinal epidural analgesia, and new anesthetic drugs, such as ropivacaine and levobupivacaine, have modified the anesthetic practice in obstetric labor analgesia. These new analgesic techniques have less or no neonatal effects when compared with traditional epidural labor analgesia. They also have less effect on mode of delivery, which may in turn affect neonatal outcome. The use of very diluted or low concentrations of local anesthetic solutions may reduce their placental passage and thus the possible subtle neonatal effects. Small doses of epidural or spinal opioids alone or combined with low doses of local anesthetics does not affect the well-being of the neonate at birth. When considering the neonatal outcome, combined spinal epidural analgesia is as well tolerated as low-dose epidural analgesia. Transient fetal heart rate changes have been described immediately after the administration of intrathecal or epidural opioids. Maternal hypotension may also occur at the onset of epidural analgesia. Whether the occurrence of transient fetal heart rate changes or maternal hypotension immediately after the epidural block may influence the neonatal outcome at birth needs verification.

A history of neuraxial administration of local analgesics and opioids

The history of intrathecal and epidural anaesthesia is in parallel with the development of general anaesthesia. As ether anaesthesia (1846) is considered the first modern anaesthetic since its use by Morton 157 yr ago, so Bier made history by using cocaine for intrathecal anaesthesia in 1898. The first published report on opioids for intrathecal anaesthesia belongs to a Romanian surgeon, Racoviceanu-Pitesti, who presented his experience at Paris in 1901. It was almost a century before the opioids were used for epidural analgesia. Behar and his colleagues published the first report on the epidural use of morphine for the treatment of pain in The Lancet in 1979. Epidural and intrathecal opioids are today part of a routine regimen for intra- and postoperative analgesia. Over the last 30 yr, the use of epidural opioids has became a standard for analgesia in labour and delivery, and for the management of chronic pain. Finally, epidural opioids have been shown to have a pre-emptive effect, when used before major surgery. We present the evolution of neuraxial anaesthesia and the history of intrathecal and epidural administration of opioids.

Itch is an unpleasant sensory experience.

The International Association for the Study of Pain (IASP) defines pain as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. In a note attached to that definition (http://www.iasppain.org.terms-p.html#Pain), the IASP further states that “unpleasant, abnormal experiences (dysesthesias) may also be pain but are not necessarily so because, subjectively, they may not have the usual sensory qualities of pain.” While everyone would agree that itch does not have the sensory qualities of pain, for those patients with intense, unrelenting itch the sensory and emotional experiences can be as unpleasant as pain. Clinical colleagues have told me anecdotal stories of patients with itch due to spinal intrathecal opioid administration who indicated a desire to stop the opioid administration because they would rather experience the pain than the itch. It is difficult to define the number of patients whose quality of life is adversely impacted by uncontrolled itch. However, as suggested in Table 1 by a partial list of dermatologic and systemic diseases that are associated with itch, it is likely that the number is quite high. Because itch does cause unpleasant sensory and emotional experiences in a large number of humans, it seems appropriate to focus more attention on efforts to understand the physiology of itch. In addition, because most current treatments for itch are quite inadequate, it also seems appropriate to attempt to develop better treatment modalities for patients suffering with intense, unrelenting itch. This topic is also of potential interest

Intrathecal opioids for combined spinal-epidural analgesia during labour.

In <25 years, intrathecal administration of opioids (i.e. spinal analgesia) has evolved from an experimental model into an important therapy for obstetric analgesia and anaesthesia. A small dose of opioid delivered into the CSF provides almost immediate relief from labour pain with minimal risks to the mother and fetus. Careful attention, and prompt treatment when needed, can ameliorate the adverse effects of fetal bradycardia, respiratory depression and pruritus. The major limitation of intrathecal opioids for labour analgesia is the short duration of effect: 90-180 minutes under ideal circumstances. To address this problem, and to increase flexibility for anaesthesia as well as analgesia, the combined spinal-epidural (CSE) technique was developed. The CSE technique involves injection of drugs into the CSF and placement of an epidural catheter. An intrathecally administered opioid provides a rapid onset of labour analgesia without motor block or significant haemodynamic perturbation. The epidural catheter allows ongoing administration of medications to maintain labour analgesia and provides a means of delivering anaesthesia for operative delivery. This review will focus on intrathecally administered opioids as used as part of CSE analgesia. Considerable research has focused on the optimum dose of opioids when delivered intrathecally, with or without adjuncts, in the CSE technique. Fentanyl and sufentanil, two of the lipophilic synthetic opioids, have emerged as the most useful. Bupivacaine, a long-acting local anaesthetic, is often added to prolong the duration of analgesia, although this tends to increase the likelihood of motor blockade of the lower extremities. Comparisons of the CSE technique with standard epidural practices have shown that both are effective means of providing analgesia during labour. Controversy revolves around the incidence of fetal bradycardia following CSE and whether this phenomenon increases the rate of operative deliveries. The rapid onset of analgesia with intrathecally administered opioids must be balanced against the added risks of dural puncture and considered in the context of the whole duration of labour. Ultimately, the decision to choose a CSE technique depends on the experience of the anaesthesia provider and the local availability of drugs, equipment and monitoring capabilities.

Understanding the physiology and pharmacology of epidural and intrathecal opioids

Epidural and intrathecal opioid administration has become an important part of contemporary medical practice in a variety of clinical settings. It has been widely assumed that any opioid placed in the epidural or intrathecal spaces will produce highly selective spinally mediated analgesia that is superior to that produced by other analgesic techniques. Unfortunately, this is simply not true. In fact, multiple opioids are currently employed for spinal use despite the fact that clinical evidence has shown that spinal administration does not produce analgesia with a selective spinal mechanism or that the analgesia produced is not superior to that produced by intravenous administration. This chapter presents the basic science and clinical data available to assist clinicians in identifying which opioids are appropriate for spinal use and which are not.

Long-term Efficacy of Continuous Intrathecal Opioid Treatment for Malignant and Nonmalignant Pain

Continuous intrathecal opioid administration via an implantable pump is an effective method of treatment for chronic pain. This retrospective study examines the long-term effectiveness of continuous intrathecal opioid treatment in patients with malignant and nonmalignant chronic pain syndromes. We reviewed charts from 81 patients with a history of permanent pump implantation between 1989 and 2000 for treatment of chronic pain due to malignant or nonmalignant causes. We conducted follow-up using telephone interviews. Of the 81 patients, 31 had placement of the pump for malignant pain and 50 had placement for nonmalignant pain. Of those with malignant pain, 30 were no longer living at the time of the study. We were unable to locate 21 of those with nonmalignant pain. Of the 30 patients who participated in the study, 24 patients continued to use the pump, and six patients had the pump removed. Follow-up ranged from 2.2 years to 7.3 years, with an average follow-up of 4.5 years. Patient age ranged from 42 years to 84 years with an average age of 64 years. Twenty-two of the 24 patients still using the pump considered it effective at relieving their pain, with an average pain relief of 62.92% ± 16.81%. Eighteen of the 24 patients required oral pain medications for breakthrough pain. All patients had had their intrathecal opioid dose increased since the original time of pump placement. Complications occurred in eight patients, including eight fractured catheters, two coiled catheters, one displaced catheter, three pump malfunctions, two displaced pumps, and two infections, one of which was meningitis. Nine pumps were replaced due to battery depletion. Eighteen of the 24 patients reported no side effects. Those reporting adverse effects named constipation, urinary retention, nausea, anorexia, light-headedness, fatigue, increased hunger, facial flushing, dry mouth, pruritus, and edema as their complaints. This study, along with previous studies of long-term continuous intrathecal opioid administration, demonstrate that it is an effective treatment modality for chronic pain of both malignant and nonmalignant origin.

Sex hormone suppression by intrathecal opioids: a prospective study.

Sexual dysfunction and low testosterone levels have been observed previously in males with chronic noncancer pain treated with intrathecal opioids. To investigate the hypothesis that intrathecal opioids suppress the hypothalamic-pituitary-gonadal axis, a prospective nonrandomized investigation of the function of this axis was undertaken. Ten males with chronic noncancer pain were evaluated for clinical and biochemical evidence of hypogonadism at baseline and during the first twelve weeks of intrathecal opioid therapy. Intrathecal opioid administration resulted in a significant (p <0.0001) reduction in serum testosterone, from 7.7 +/- 1.1 (mean +/- SEM) nmol/L at baseline to 2.0 +/- 0.7, 2.8 +/- 0.5, and 4.0 +/- 0.9 nmol/L at 1, 4, and 12 weeks, respectively. This was associated with a reduction in libido and potency. Luteinizing hormone and follicle-stimulating hormone levels remained within reference ranges, indicating central rather than peripheral suppression. Administration of intrathecal opioids may result in hypogonadotrophic hypogonadism. As part of the consent for therapy process, patients should be informed about this effect and its management. With long-term intrathecal opioid administration, the hypothalamic-pituitary-gonadal axis should be monitored. Where indicated, testosterone replacement should be undertaken to improve sexual function and prevent the potential metabolic effects of hypogonadism, in particular, osteoporosis.

Intrathecal opioids versus epidural local anesthetics for labor analgesia: A meta-analysis

Background and Objectives: Some anesthesiologists contend that intrathecal opioid administration has advantages over conventional epidural techniques during labor. Randomized clinical trials comparing analgesia and obstetric outcome using single-injection intrathecal opioids versus epidural local anesthetics suggest that intrathecal opioids provide comparable analgesia with few serious side effects. This meta-analysis compared the analgesic efficacy, side effects, and obstetric outcome of single-injection intrathecal opioid techniques versus epidural local anesthetics in laboring women. Methods: Relevant clinical studies were identified using electronic and manual searches of the literature covering the period from 1989 to 2000. Searches used the following descriptors: intrathecal analgesia, spinal opioids, epidural analgesia, epidural local anesthetics, and analgesia for labor. Data were extracted from 7 randomized clinical trials comparing analgesic measures, incidence of motor block, pruritus, nausea, hypotension, mode of delivery, and/or Apgar scores. Results: Combined test results indicated comparable analgesic efficacy 15 to 20 minutes after injection with single-injection intrathecal opioid administration. Intrathecal opioid injections were associated with a greater incidence of pruritus (odds ratio, 14.01; 99% confidence interval, 6.9 to 28.3), but there was no difference in the incidence of nausea or in the method of delivery. Conclusions: Published studies suggest that intrathecal opioids provide comparable early labor analgesia when compared with epidural local anesthetics. Intrathecal opioid administration results in a greater incidence of pruritus. The choice of technique does not appear to affect the method of delivery. Reg Anesth Pain Med 2002;27:23-30.

Pharmacology (81)

Endocrine consequences of long‐term intrathecal administration of opioids. (University of Antwerp, Edegem, Belgium) J Clin Endocrinol Metab 2000;85:2215–2222.This study involved 73 patients (29 men and 44 women) receiving opioids intrathecally for nonmalignant pain who 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) 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 &lt; 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 &lt; 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 &lt; 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 &lt; 0.001) and FSH (P = 0.012) levels were found. The 24‐h urinary free cortisol excretion was below 20 μg/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 μg/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 μg/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. Conclude 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.

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

Disease-specific and generic health outcomes: a model for the evaluation of long-term intrathecal opioid therapy in noncancer low back pain patients.

The present study provided comprehensive characterization of the long-term outcomes of intrathecal opioid administration via a drug administration system (DAS) in chronic pain patients with predominantly low back pain. A conceptual framework based on multidimensional outcomes is proposed using both disease-specific and generic measures. Pre-post longitudinal data were collected in a retrospective fashion on 38 patients receiving intraspinal opioid therapy for a minimum of 36 months (average = 50 months). Disease-specific measures included magnitude of infused opioid, side effects/complications, pain ratings, McGill Pain Questionnaire, Beck Depression Inventory, Oswestry Disability Questionnaire, and patient estimated improvement in pain (0-100%). Generic measures of health included the Quality of Well-Being Scale, Medical Outcomes Study (MOS) Short Form 36 (SF-36), return to work, patient estimated improvement in functioning, overall patient satisfaction, and family opinion of patient improvement. Disease-specific outcomes. Patients receiving long-term intrathecal opioid administration showed a sixfold increase in morphine equivalents infusion rates across time. DAS patients showed a small but significant decrease in pain ratings from pre-treatment levels. Following 3 years or more of intrathecal opioid infusion, patients endorsed high pain levels on the McGill Pain Questionnaire, severe levels of disability via the Oswestry Disability Questionnaire, mild levels of depression based on the Beck Depression Inventory, and multiple side effects associated with the intrathecal opioids and complications related to the infusion system. On retrospective questioning, patients receiving long-term intrathecal opioid administration reported an average of 64% improvement in their pain and 48% improvement in functioning. Family members of patients reported that they observed on average a 61% improvement in patient's pain. Generic outcome measures. On the Quality of Well-Being Scale, patients reported significantly lower health-related quality of life than health maintenance organization enrollees with no known chronic condition and patients with rheumatoid arthritis (p < 0.001). On the MOS SF-36, patients reported significantly lower physical functioning than the U.S. general population, patients with uncomplicated medical conditions, diabetes-type II patients, and congestive heart failure patients. Mental functioning was comparable to the U.S. general population (p > 0.001). Fourteen percent of patients were working following implantation. Eighty-nine percent of patients reported good to excellent satisfaction with the long-term intrathecal opioid therapy. Results from this study revealed differences in findings across the outcome measures, highlighting the complexity of intrathecal opioid therapy. Generally, patients after 3 years or more of intrathecal opioid therapy can be characterized as hav ing substantially impaired physical functioning with a high prevalence of side effects. Despite poor physical functioning, patients endorsed relatively good mental health status with only mild depressive symptoms. Longitudinal pain ratings showed a modest decrease from pretreatment levels. On retrospective evaluation, patients and their family endorsed high levels of pain relief secondary to intrathecal therapy. Overall, findings support that intrathecal opioid therapy provides some therapeutic benefit although substantial physical impairment continues to cause debilitation in the patient population.

EPIDURAL AND SPINAL AGENTS FOR POSTOPERATIVE ANALGESIA

The discovery of opioid receptors and the subsequent development of the technique of epidural and intrathecal opioid administration are undoubtedly two of the most significant advances in pain management in recent decades. The use of spinal opioids is widespread and increasing. The technique is used widely to treat intraoperative, postoperative, traumatic, obstetric, chronic, and cancer pain. Newer developments include the increasing use of combined local anesthetics and opioids or nonopioids and also PCEA, particularly in the obstetric population. Meta-analysis of controlled trials has demonstrated improved pulmonary outcome in patients receiving epidural postoperative analgesia. Although rare, respiratory depression continues to be a major problem of the technique. None of the currently available opioids is completely safe; however, extensive international experience has shown that patients receiving spinal opioids for postoperative analgesia can be safely nursed on regular wards, provided that trained personnel and appropriate guidelines are available. The importance of a good acute pain service to provide the safe and effective use of spinal opioids cannot be overemphasized.

Problems of long-term spinal opioid treatment in advanced cancer patients

Epidural and intrathecal techniques are well established techniques in cancer pain. However, several questions remain unresolved. The several problems of long-term spinal opioid treatment in advance cancer patients were reviewed. Indications for the use of spinal opioids include patients treated by systemic opioids with effective pain relief but with unacceptable side effects, or unsuccessful treatment with sequential strong opioid drug trials despite escalating doses. Therefore, the previous aggressive treatment with systemic opioids would leave as failures patients with difficult pain syndromes unresponsive to opioids. The choice of external or totally implanted delivery systems is based on different clinical considerations. The use of externalized tunneled intrathecal catheters has not been associated with higher rates of complications and is easier to place and use at home in debilitated patients late in the course of their disease. The intrathecal administration has a lower incidence of catheter occlusion, lower malfunctioning rate, lower dose requirement, and more effective pain control. Due to the lower daily doses and volumes, intrathecal treatment proved to be more suitable for treatment at home by a continuous infusion than the epidural treatment. Advantages of infusion techniques are more evident when using local anesthetics, since intermittent administration of bupivacaine often results in motor paralysis and hemodynamic instability. Morphine is the opioid of choice. An epidural dose of 10% of the systemic dose is often used. However, intrathecal administration of opioids and bupivacaine may substantially improve pain relief in patients unresponsive to high epidural doses of these drugs, Bupivacaine-induced adverse effects, including sensory deficits, motor complaints, signs of autonomic dysfunction or neurotoxicity have been reported to not occur with bupivacaine doses less than 30–60 mg/day. Adjuvant drugs may further improve analgesia. Different ranges of technical complication rates have been reported in the literature, most of them being associated with epidural catheters. Subcutaneous tunneling and fixation of the catheter, bacterial filters, minimum changes of tubings, careful exit site care weekly, site protection and monitoring of any sign of infection to prevent infection, and training for family under supervision, are recommended. Areas for additional research include the use of spinal adjuvants, the ideal spinal morphine-bupivacaine ratio, methods to improve spinal opioid responsiveness and long-term catheter management with appropriate home care programs.