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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