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Monday, 12 September 2011

The Management of Pain From Collapse of Osteoporotic Vertebrae With Continuous Intrathecal Morphine Infusion


Blackwell Publishing Inc



The Management of Pain From Collapse of


Osteoporotic Vertebrae With Continuous


Intrathecal Morphine Infusion



 



ABSTRACT



Objectives.



Vertebral fractures are the most common consequences of severe osteoporosis. The chronic pain from


collapse of osteoporotic vertebrae affects quality of life (QoL) and autonomy of patients. The management of


pain with oral or transdermal opiates can cause severe side-effects. Continuous intrathecal administration of morphine


through an implantable pump might represent an alternative therapy to conventional oral or transdermal


administration of opioids and has some advantages and disadvantages for pain relief and improvement in QoL


when compared to conventional opioid delivery. It is our objective to report our experience using intrathecal


delivery of analgesics in a population of patients with refractory pain due to vertebral fractures.



Materials and


Methods.


In 24 patients, refractory to conventional delivery of opioids, we used intrathecal analgesic therapy.


To test for efficacy and improvement in QoL, we administered the visual analog scale (VAS) for pain and the


Quality of Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO). Before patients


were selected for pump implantation, an intraspinal drug delivery trial was performed to monitor side-effects


and responses to intrathecal therapy.



Results.


Significant pain relief was obtained in all implanted patients.


Using the QUALEFFO, we observed significant improvement of all variables such as QDL (quality of daily


life), DW (domestic work), ambulation, and PHS (perception of health status), before and after one year after


pump implantation. With intrathecal morphine infusion, none of the 24 patients required additional systemic


analgesic medication. The mean morphine dose during the spinal trial was 11.28 mg/day, 7.92 mg/day at


pump implantation, and 16.32 mg/day at one-year follow-up.



Conclusions.


Our results show that intrathecal


administration of morphine efficiently relieves the symptoms of pain and improves QoL. Continuous intrathecal


administration of morphine appears to be an alternative therapy to conventional analgesic drug delivery


and has advantages in those patients who have severe side-effects with systemic administration of analgesics.



KEY WORDS:


Continuous intrathecal morphine infusion, osteoporosis, vertebral fracture.



Introduction



Osteoporosis is a metabolic disease of bone tissue


characterized by the reduction of bone mass. The


Consensus Conference of Hong Kong, in 1993,


defined osteoporosis as systemic pathology of the


skeleton with reduction of bone mass and microstructural


deterioration of bone tissue, resulting


in increased bone fragility and risk of fracture


(1). According to the World Health Organization,


osteoporosis is a reduction of the bone density


mass (BDM). With osteoporosis, bone density


scans show a reduction (T-Score-2.5) of at least


one standard deviation (SD) when compared to


the average value of the bone density of a young


healthy individual, used as a reference. This


reduction corresponds to a loss of 25–40% of


bone mass (2).


Osteoporosis occurs as either a primary pathology


or secondary to other pathologies (3). The


risk of primary osteoporosis increases with age.


Peak bone mass density is reached at age of 20–


30 years, and, by middle age, bone mass starts to


slowly decrease by 1% per year. Vertebral loss of


bone has a different pattern and different speed


of deterioration. Deterioration starts at the age


of 20 years and continues steadily at a speed of


up to 7% every 10 years in women and less than


2%, per decade, in men (4,5).


Vertebral fracture is the most common consequence


of osteoporosis (6). The incidence of


vertebral fractures is 5% in women at age of 50


years with a frequency of 0.5% per year, 25% in


women at age of 80 years with a frequency of


3% per year, and 64.3% in both sexes at the age


of 90 years (7,8). Vertebral fractures are mostly


localized at the thoracic level around T8 and at


the thoraco-lumbar junction T12–L1. These are


the most critical areas from a biomechanical


view point because the paravertebral muscles at


those levels are not capable of sustaining the


weight increase that is common with age (9).


Changes in vertebral shape due to osteoporosis


are classified into three groups: wedge deformities,


compression fractures, and biconcave or fish


deformities. Wedge fractures are often situated


in the central to lower part of the spine, biconcave


deformities in the lumbar vertebral bodies, and


compression fractures in the lower part of the


thoracic spine (10). Very intense acute pain of


vertebral fracture, responsive to analgesic therapy


or vertebroplastic and kyphoplastic interventions,


is only reported in 25–30% of cases (11,12) and


is of short duration, lasting between six and


ten weeks.


It is now well-established that the frequency


of new vertebral fractures is four to seven times


higher within 6–18 months in persons with a


pre-existing vertebral fracture when compared to


persons without pre-existing vertebral fracture.


This risk is independent of the bone density


(13,14). The pain due to vertebral fracture becomes


chronic within four years (15,16)


Repeated vertebral fractures are responsible


for chronic pain. Chronic pain from these fractures


is not only of bone origin but also it is due to


stretching of muscles, tendons, and ligaments


and due to arthritis of the articular surface. The


arthritis of the articular surfaces is responsible


for postural and anatomical modifications that


can, later, be the cause of a secondary arthrosis


(17). Often vertebral fractures are associated


with increased general morbidity, decrease of


psychomotor ability, disability, and loss of personal


autonomy (17–19).


New molecules for therapy of osteoporosis


such as diphosphonates and raloxifene are able


to improve the density and quality of bone, but


are not analgesic for persons with fracture. The


treatment of chronic pain due to vertebral


fracture is difficult and might require the use of


systemic opioid analgesics (20), but the administration


of these analgesics is associated with


side-effects in some individuals (21). In addition,


osteoporosis is a disease of older people and is


often associated with other chronic comorbidities


such as arthrosis, arterial hypertension, diabetes,


coronary artery disease, neurologic diseases,


and respiratory diseases. Therefore, pharmacologic


interactions can be problematic in this


older population (22,23). Gastrointestinal and


renal toxicity of anti-inflammatory therapies is


well documented (24). The use of calcitonin


can result in nausea, vomiting, flushing, and


dizziness (25).


The management of pain with opioids for


vertebral fractures reveals rapid amelioration of


pain and improved mobility (20). Transdermal


fentanyl is useful for the treatment of severe back


pain caused by osteoporosis, but 20% of patients


suffer from adverse events, most commonly


nausea, vomiting, or dizziness (26). In this article, we


discuss our treatment of refractory chronic pain due


to vertebral fractures with implantation of drug


delivery pumps for the intrathecal infusion of morphine


in patients who do not tolerate systemic


opioids because of severe side-effects and, in whom,


vertebroplasty or kyphoplasty are not indicated.



Material and Methods



Patients



We treated 24 patients, 19 women and 5 men,


with an average age of 74.3 years. Our inclusion


criteria in this study were:


• advanced osteoporosis without recent vertebral


fracture;


• visual analog scale (VAS) for pain > seven after


three months of noninvasive therapies;


• VAS > seven after one month of oral and


transdermal administration of opioids;


• severe side-effects to systemic opioids such as


vomiting, itching, constipation, or urinary retention,


all resistant to pharmacological therapy;


and


• absence of psychologic barriers to success and/


or drug addictions.


A positive response to a trial for intrathecal


delivery of opioid, a response of > 50% improvement


in the VAS, performed by insertion of an


externalized spinal catheter for the intrathecal


administration of morphine, was necessary before


implantation of a permanent system, including


an intrathecal catheter and pump. All patients were


diagnosed with advanced osteoporosis resulting


in severe pain.



Evaluations



At first visit, all patients underwent magnetic


resonance imaging to evaluate and stage the level


of vertebral fractures to aid in patient selection


for a trial of intrathecal therapy. History and physical


examinations were performed to correlate


location of pain with the level of the fractures


and to collect data on side-effects of pharmacologic


treatment. At this visit, we administered a


VAS (27) and the Quality of Life Questionnaire


of the European Foundation for Osteoporosis


(QUALEFFO) (28), which is specific for quality of


life (QoL) issues in this group of patients. With


QUALEFFO, patients are asked to answer 30


questions about their pain (duration, frequency,


intensity, pharmacologic treatment), daily activities


(washing, dressing, sleeping), domestic works


(cooking, cleaning, shopping), ambulation (going


up stairs, walking for 100 m, bending on one’s


knees, bending at the trunk), and general perception


of health (report of own health conditions).


Each answer is tied to a score ranging between


1 and 5. The minimum sum of each score is 30,


which is indicative of a good health status. The


maximum sum of each score is 150, which is


indicative of poor health. The relevance of


QUALEFFO has been validated in a multicentered


study performed in seven countries (28). To


obtain statistical data, the VAS was administered


before, during, and at end of trial for intrathecal


therapy, after pump implantation, and at one-year


follow-up. The QUALEFFO was administered


before the trial, after pump implantation, and


one year after pump implantation.



Intrathecal Trial



One week after the initial visit, we started the trial


of intrathecal morphine. Before this trial, in


patients treated with oral morphine, the oral dose


was reduced by 50%. The continuous, initial


infusion dose of morphine was 0.5–1 mg in 24 hours


using an intrathecal infusion via an externalized


catheter. During the first three days of the trial,


all patients were hospitalized. The oral administration


of morphine was gradually tapered and


the infusion dose was increased by 1 mg/day until


the VAS was reduced by, at least, 50%. At day 3,


after the initiation of this trial, patients were


discharged. At the sixth day from the beginning


of the trial, all patients returned to the pain unit


for trial follow-up. We considered the trial over


when the VAS score was reduced by 50% and


the dose reducing the pain by 50% was stable


for at least three days. Data collected during the


trial included morphine dosing and the development


of side-effects, if any (Table 1). Nausea,


vomiting, itching, and/or constipation were treated


with antiemetics, antihistaminics, and laxatives,


respectively. Our screening trials had the following


objectives:


• to monitor and report, in the clinical record, all


patient side-effects of therapy such as nausea,


vomiting, itching, sleepiness, constipation, and/


or urinary retention;


• to determine initial dose requirements;


• to establish the appropriateness of therapy;


• to daily monitor pain relief, if any, using a VAS


for pain; and


• to monitor functional scores using the


QUALEFFO questionnaire, administered before


the trial, after pump implantation, and at oneyear


follow-up.


The delivery system used for this study was a


constant-flow Archimedes infusion pump designed


for the continuous intrathecal delivery of analgesic


medications (Codman, Johnson & Johnson,


Raynham, MA, USA). These titanium pumps


utilize a butane drive-medium that creates a


specific pressure at normal body temperature


and above and places a constant pressure on the


exterior surface of the reservoir. The flow infusion


of the system that we used was 0.5 mL/24 hours


and the reservoir capacity was 20 mL.


In those patients having successfully passed the


intrathecal trial, once the pump was implanted, the


initial morphine daily dose was reduced by 20%


when compared to the dose at trial, QUALEFFO,


side-effects, and morphine doses were reviewed and


recorded (). After three to five days,


the morphine dose was increased to the dose at


the end of the trial. At one year from pump


implantation, data from the VAS, QUALEFFO,


and morphine dosing were collected ()



Statistical Analysis



Statistical processing (i.e., comparisons between


the variable levels, recorded at different intervals,


performed by means of a paired nonparametric


procedure [Wilcoxon]), was implemented using


the statistical package StatGraphics version 4.0


(STSC Inc., Rockville, MD, USA). If not otherwise


specified an (I type) error level less than 5% was


deemed significant.



Results



We treated 24 patients between the ages of 67 and


83 years, average age 74.3 years, with intrathecal


infusion of morphine via an implanted, nonprogrammable


pump. All patients were diagnosed


with chronic pain due to vertebral collapse secondary


to advanced osteoporosis. Prior to implant,


all patients were treated conservatively with the


systemic delivery of analgesic drugs: five patients


were treated with transdermal fentanyl, 50


g/hour;


five patients were treated with codeine 90 mg/day


and paracetamol 1500 mg/day; five patients were


treated with oral morphine, 60 mg/day; two


patients were treated with epidural morphine,


2 mg/day; four patients were treated with tramadol,


200 mg/day; and three patients were treated with


ketorolac 60 mg/day and oral morphine 50 mg/day


(Table 2). Side-effects of systemic opioids, in


our population, included itching in 12.5% of


patients, vomiting in 33.3% of patients, urinary


retention in 8.3% of patients, and sleepiness in


4.1% of patients.


The mean VAS value before trial was 8.7 cm.


After pump implant, the mean VAS score was


3.6 cm and after one year, 1.9 cm. The mean


functional score (QUALEFFO) before trial was


114.7. After pump implant, the mean QUALEFFO


score had fallen to 92.1, and, after one year, the


mean QUALEFFO score fell to 79.1 (Table 2).


The mean morphine dose, at trial, was 0.47 mg/


hour, which corresponded to a mean VAS value


of 3.7. The mean morphine dose used at pump


implant was 0.33 mg/hour and the mean morphine


dose after one year from the pump implantation


was 0.68 mg/hour (Table 1).


Side-effects reported during the trial included


vomiting in five patients and itching in three


patients that were treated successfully with antiemetics


and antihistaminics, respectively. After


pump implantation, nausea occurred in only


three patients. There was a wound infection


in one case that required antibiotic therapy;


in another case, there was delayed healing. In


two patients, catheter dislocation necessitated


reinsertion of the catheter. No patients required


additional oral/transdermal dose of analgesics.



Statistical Results



The comparison of QUALEFFO variables and VAS


values before the screening test and one year


from pump implantation shows high statistical


differences (Table 3).



Discussion



It is estimated that the severity of osteoporosis


and its clinical consequences such as pathologic


fractures will increase fourfold in the next halfcentury


because of the increase in worldwide


population and longevity of these populations


(29). The majority of patients with vertebral


fractures respond favorably to traditional treatment;


however, there are some patients who fail


conservative therapy and suffer from prolonged


pain and immobility (29). The chronic pain due


to osteoporotic vertebral collapse has severely


negative social and economic effects. Intrathecal


administration of opioids represents a reasonable,


albeit, expensive alternative opioid therapy in


patients not responding to traditional therapy


and has advantages when compared to systemic


administration (i.e., less dosing and less systemic


side-effects). Intrathecal administration of morphine


gives a lower incidence of dependence,


tolerance, and side-effects when compared to


systemic administration (30–32). Side-effects of


intrathecal administration of opioids can be prevented


by starting the treatment with lower doses


and by increasing it gradually and administering


adjuvant medications, such as bupivacaine or


clonidine (33,34).


The loss of bone mass related to age is due to


genetic as well as environmental factors (35). In


postmenopausal women, there is an accelerated


bone turnover with increased demineralization (36).


From the age of 70 years on, senile osteoporosis


may occur, involving men, as well (37). The most


important etiologic factors in senile osteoporosis


are deficit of calcium and vitamin D, sedentary


lifestyle, and drop in gonad function in both


sexes (38). Therefore, osteoporosis is pathology


of advanced aging, which affects both QoL and


autonomy of affected individuals, especially in the


presence of fractures and vertebral compression


(15,39). Only one vertebral fracture is sufficient


to increase the risk of severe dorsal chronic pain in


a patient (40), and this risk increases exponentially


with the number of collapsed vertebrae (41,42).


Several recent case series (43–45) have reported


significant pain relief with percutaneous vertebroplasty


(PVP) in as many as 90% of cases of


osteoporotic vertebral compression fractures. The


mechanism of pain relief from PVP remains


uncertain; however, stabilization of microfractures,


vascular, and chemical factors have been proposed


as mechanisms (46). Although, subjective failure


of conservative therapy is generally an indication


for the procedure, the time from fracture to PVP


ranges from two weeks to at least several months


(47). Some authors have suggested that PVP is


effective in reducing analgesic requirement, but


this effect is slightly blunted in patients who


require opioids before the procedure and in


those who have older fractures (47). In our


study population, patients that qualified for PVP


had lack of efficacy to oral and/or transdermal


opiates or had severe side-effects to the systemic


administration of opioids. Moreover, the presence


of radiologic signs for old vertebral fractures was


not an indication for vertebroplasty. Potential


documented clinical complications of PVP include


infections, bleeding, back pain, rib fracture,


pulmonary embolism, pneumothorax from punctured


lung, fever, optic neuritis, and various


other neurologic complications (48,49).


Kyphoplasty is suggested by many authors to


improve, either vertebral body height or kiphosis


and pain in patients with recent vertebral fractures


(50). Some studies on kyphoplasty show an immediate


significant improvement in pain but no


improvement in QoL at two-year follow-up (51,52).


A recent review of side-effects of kyphoplasty shows


a great number of severe complications (49).


In our study changes in intrathecal doses were


based on pain reporting of our patients. In general


the mean morphine dose during the trial was


11.28 mg/day. At pump implantation, the mean


morphine dose was 7.92 mg/day and, after oneyear


follow-up, the dose was 16.32 mg/day. In our


series, the morphine dose for the greater number


of patients with nonmalignant pain needed to


be increased over the duration of follow-up to


maintain adequate pain control. Yaksh and Onofrio


(53) observed a similar time-dependent dose


escalation in malignant pain. This escalation


of dosing was in contrast to Winkelmuller and


Winkelmuller’s observation that doubling of the


initial dose occurred in only 27% of their patients


(54). In our results, the average intrathecal dose of


16.32 mg/day, at one-year follow-up, was comparable


to the 13.19 mg/day reported by Paice


(55), where malignant pain and non-cancer pain


patients had similar doses, except for the initial


dose, which was higher in malignant pain patients.


In our results, the mean percentage pain relief


was 68%. In Paice’s (55) retrospective, multicenter


study, the mean percentage pain relief


was 61% in patients with malignant and noncancer-


related pain. They observed that patients


with somatic pain, as in our study, tended to have


greater relief of pain with intrathecal therapy,


than did patients with other types of pain.


Pharmacologic complications were common


immediately after the initiation of therapy, but


for the most part resolved with standard medical


management, during the first three months. The


most persistent complication was nausea, found


in 12% of our patients. In our study, unlike those


reported in younger patients (55–57), there were


no reports of sexual disturbances, such as loss of


libido and amenorrhea. Our results confirmed


those of previous reports that intrathecal morphine


can be administered long-term without serious


pharmacologic complications (58).


Our results indicated that the functional score


for QoL (QUALEFFO) tended to improve after


the initiation of intrathecal therapy and tended


to remain improved for at least 12 months.


Similarly, Winkelmuller and Winkelmuller (54),


in a recent retrospective review of 120 patients,


reported that 81% of their patients experienced


global improvement in QoL with chronic intrathecal


morphine infusion at follow-up ranging


from six months to six years.


Finally, in terms of device safety, previous reports


of chronic intrathecal delivery with a totally


implanted infusion system have been generally


good and the incidence of complications experienced


in the present study was in agreement with


those of earlier studies (54,59,60). Most devicerelated


complications were associated with the


implanted intrathecal catheter, especially migration


of the catheter from the intrathecal space,


and cerebrospinal fluid leakage. In one case, a


wound infection developed and was treated


successfully with intravenous antibiotics, without


pump removal. In this series, all patients were able


to control their pain with intrathecal opioid


therapy alone.


The use of opioids given systemically, orally or


transdermally, can control pain, but is associated


with severe physical and psychologic side-effects in


some individuals (61). Intrathecal administration


of opioids should be used in those patients


who have failed conventional delivery of opioids


according to the analgesic ladder as described


by the World Health Organization analgesic guidelines


(62–64). Morphine is the most commonly


used opioid administered into the subarachnoid


(intrathecal) space (65,66), and it is the most


commonly selected drug for trial initiation (67).


Intrathecal administration of morphine is 100


and 300 times more effective when compared to


intravenous and oral administration, respectively,


and 10 times more efficient when compared to


epidural administration (32). The intrathecal


administration of morphine has pharmacokinetic


and pharmacodynamic advantages, reducing the


incidence of side-effects and producing relief


of pain at substantially lower doses (68,69). This


effect of intrathecal morphine, a μ-receptor


agonist, is related to the presence of μ receptors


in the dorsal horn of the gray matter of the spinal


cord, its high hydrophilia and low lipophilia,


and the high affinity of morphine to these


receptors (70).



Conclusions



With intrathecal therapy, as shown by this study,


patients do derive relief from pain and regain a


good QoL. In our experience, complications and


side-effects related to pump implantation and


continuous infusions for at least one year were


minor and transient. It is our belief based on this


evaluation that the intrathecal administration of


opioids should be considered as another resource


for patients with osteoporotic vertebral fracture


and pain when all traditional treatments have


failed or if traditional treatments are inadequate


after a reasonable period of trial time.



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