Gabapentin as an Adjuvant Analgesic with Opioids for the ...anesthai.org/public/rcat/Documents/journal... · Therefore, adjuvant drugs; mainly antidepressants or anticonvulsants,

Volume 40 Number 4 October – December 2014 Thai Journal of Anesthesiology 237

Gabapentin as an Adjuvant Analgesic with Opioids

for the Management of Metastatic Bone Pain:

Randomized, Double - Blind, Placebo - Controlled

Crossover Trial

* กลุ่มงานวิสัญญีวิทยา, *กลุ่มงานอายุรกรรม โรงพยาบาลมหาราชนครราชสีมา จ.นครราชสีมา,

** ภาควิชาวิสัญญีวิทยา คณะแพทยศาสตร์โรงพยาบาลรามาธิบดี มหาวิทยาลัยมหิดล กรุงเทพ

จตุพร ถ่อนสันเทียะ, พ.บ.*, วราภรณ์ ไวคกุล, พ.บ.**,

วันทกานต์ วงศ์วิกรม, พ.บ. *, ครองกมล สีหบัณฑ์, พ.บ. ***

Abstract: Gabapentin as an Adjuvant Analgesic with Opioids for the Management of

Metastatic Bone Pain: Randomized, Double - Blind, Placebo - Controlled Crossover

Trial

Jatuporn Thonsontia, M.D.*, Waraporn Waikakul, M.D.**,

Wantakan Wongwikrom, M.D.* Khrongkamol Sihaban, M.D.* **

Department of Anesthesiology*, Department of Internal Medicine***, Maharat Nakhon

Ratchasima Hospital, Nakhon Ratchasima 30000

Department of Anesthesiology**, Faculty of Medicine, Ramathibodi Hospital, Mahidol

University, Bangkok 10400, Thailand.

Background: Bone metastasis usually

causes severe pain in cancer patients. The solely

use of opioid may be inadequate or exert intolerable

side effects. Experts suggested the use of analgesic

adjuvants. However, gabapentinoids; anticonvulsants

used to treat neuropathic pain, are frequently added

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238 วิสัญญีสาร ปีที่ 40 ฉบับที่ 4 ตุลาคม – ธันวาคม 2557

to the pain control regimen. There is no evidence

that gabapentin is useful in controlling pain due

to bone metastasis. Objectives: To assess the

analgesic efficacy and side effects of gabapentin

900 mg/day compared with placebo as add-on

therapy to opioids in patients with metastatic bone

pain. Methods: The study is a randomized, double-

blinded, fix - dose, placebo-controlled crossover

trial. Thirty - two patients, who were on stable dose

of opioids for the treatment of metastatic bone

pain, were randomly allocated into 2 treatment

groups, 16 each. Patients in each group received 2

treatment periods with 4 - day washout in between;

10 days for gabapentin or matching placebo and

reciprocal. The subjects took either gabapentin 900

mg/day or placebo in identical pattern. Overall

time was 24 days during the double-blind treatment

period. The subjects were contacted by phone

on day 2, 4, 8, 16, 18 and 22 following a dose

adjustment to assess compliance and tolerability.

The subjects were followed up at clinic on day 1,

15 and 25. Outcome comparisons were; average

pain score reduction on day 1 and day 8 of each

period, percentage of patients who have average

pain score reduction ≥ 3, amount of rescue

analgesic and side effects. Results: Of the 32

patients enrolled, 30 patients received gabapentin

and 26 patients received placebo. Analysis of

covariance (ANCOVA) on the intention-to-treat

basis showed no significant difference in average

pain score reduction between gabapentin and

placebo group; 2.77 ± 2.10 vs 2.46 ± 1.25, (p =

0.533). Percentage of patients who had average

pain score reduction ≥ 3 during follow-up days

were not different (53.23 ± 2.81 vs 47.44 ± 3.53),

p = 0.586. Rescue medication for breakthrough

pain was not different (p = 0.607). Finally,

incidence of side effects; sedation, dizziness,

nausea, vomiting and constipation, were not

different. Conclusions: Adding gabapentin to

opioid analgesic did not accentuate efficacy of

opioids in relieving pain in metastatic bone pain

patient.

Key words: Gabapentin, metastatic bone pain,

opioids

Introduction Bone is one of the most common metastatic

site of common tumors such as breast, lung and

prostate cancers.1,2 In addition to severe pain, bone

metastasis is associated with pathologic fractures,

spinal cord compression, hypercalcemia, reduced

quality of life, decreased physical-social function

and increased depression and anxiety.3,4

The first line treatment for metastatic bone

pain is analgesics. The World Health Organization

recommended 3-step ladders starting with non-

opioids to relieve mild to moderate pain. If pain

still persists or increases, step 2 weak opioids such

as codeine or tramadol is added. For persistent or

moderate to severe pain, strong opioids such as

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morphine, fentanyl or methadone are used.

Background pain is usually controlled by slow-

released opioids; such as morphine sulfate

sustained release tablet (MST continus® and

kapanol®) or fentanyl transdermal patch, which

should be given around the clock. Breakthrough

pain may be treated with an immediate release

opioid.5, 6

In many patients, if the bone pain is

localized, radiotherapy is the treatment of choice.5

But for some patients who have widespread lesions,

bisphosphonates is an alternative. Bisphosphonates

inhibit osteoclast activity. They decrease hyper -

calcemia and the subsequent risk of fractures

in addition to reducing bone pain.7 Usually,

moderate-to-high doses of opioids may be required

to achieve pain control in these patients. Opioids

have significant dose-dependent side effects such

as nausea, vomiting, sedation and constipation.

Therefore, adjuvant drugs; mainly antidepressants

or anticonvulsants, are used to improve analgesic

effectiveness with less opioids doses.

Even though tumor is confined in the bone,

metastatic bone pain is caused by tumor - derived

inflammation. In addition, the products released by

the tumor which injure the primary afferent nerve

fibers that innervate the bone are also the causes of

pain. These signify neuropathic mechanisms.8,9

The metastatic bone pain were both ongoing and

movement-evoked pain. Opioids are mainly

effective in background pain, which may explain

why high doses of opioids do not provide sufficient

pain relief.

Since the pain is not only nociceptive but

also neuropathic, mechanism-based therapy which

is the addition of anticonvulsant/antidepressant

into opioids regimen is reasonable. Data from

randomized study of pregabalin in patients with

cancer-induced bone pain indicates that pregabalin

may reduce metastatic bone pain (interim analysis).10

Gabapentin also has analgesic effect in several

nonmalignant chronic neuropathic pain and cancer

pain that has neuropathic component when

combined with opioid analgesics.11 Additionally,

previous study found that gabapentin attenuated

both ongoing and movement-evoked bone cancer-

related pain behaviors in animals. However, it did

not influence tumor growth or tumor-induced bone

destruction.12 Currently, no clinical data suggests

that gabapentin can enhance opioids analgesia but

the analgesic benefit of this popular practice is the

off-label use. Therefore, the aim of this study is to

assess the efficacy and safety of adding gabapentin

to opioid analgesia in relieving metastatic bone

pain.

Methods The study was a randomized, double-

blinded, fix - dose, placebo - controlled crossover

trial. It was approved by the Institutional Review

Board of Maharat Nakhon Ratchasima Hospital.

Informed consent was obtained from all the

patients. The enrolled patients were patients with

metastatic bone pain, both in the inpatient and

outpatient departments, at Maharat Nakhon

Ratchasima Hospital from September 2013 to

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October 2014.

Inclusion criteria were: (1) age ≥ 18 years,

(2) cancer with at least one metastatic bone lesion

and bone pain was the major pain. Bone metastasis

was established by radiographic confirmation such

as CT scan, MRI and bone scan. (3) Average pain

score in the last 24 hours was ≥ 4 (assessed on a 0

to 10 numerical rating scale (NRS) at the screening

visit. (4) Life expectancy was ≥ 30 days and

Palliative Performance Scale (PPS) was ≥ 3013. (5)

On regular and stable dose of basal opioids. Stable

opioid use was defined as constant for at least 24

hours with rescue morphine sulfate solution (MSS)

≤ 3 doses/day. And finally, (6) opioid related side

effects was ≤ Grade 2 of Common Terminology

Criteria for Adverse Events (CTCAE) Version

4.0.14

Exclusion criteria were hypersensitivity to

gabapentin, unable take oral medication, creatinine

clearance < 60 mL/min (calculated by the Cockcroft-

Gault equation), gabapentin ≥ 900 mg/day

or pregabalin ≥ 150 mg/day consumption at

screening, pathologic fracture, spinal cord com -

pression or cauda equina syndrome, chemotherapy

within 2 weeks before screening15 and radiotherapy

to the pain-producing lesion within 1 month before

screening.15

Figure 1 and 2 show scheme of the study.

Patients were randomly allocated into 2 treatment

groups by computer in a non - stratified block - of -

four. Each group of patients received 2 treatment

periods with 4 - day washout in between; gabapentin

or matching placebo. Study medications were in

identical appearance capsules containing either 300

mg of gabapentin (Neurontin®, Pfizer) or placebo.

They were prepared in sealed envelopes by the

hospital pharmacist who was not involved in the

study. All participants and researchers were

blinded to the group allocation. The treatment

phase started on the day of the screening visit (day

1). In addition to the aforementioned inclusion and

exclusion, the patients were screened for ongoing

non-opioid or gabapentinoid use and washout for 4

days was done before recruitment. At first visit, the

patients were taught about how to complete daily

pain diary and the use of rescue analgesics by p.r.n.

doses of MSS if NRS was ≥ 4. The pain diaries

were filled daily by the patient or their caregiver.

During the study, the patients took either

gabapentin (300 mg) or placebo in identical

pattern; at bed time on day 1, bid on day 2. If the

patients tolerated, the doses were increased to

3 times a day on day 3 through day 8. Day 9 and 10

were the tapering off days; bid and OD respectively.

Day 11 through day 14 were the washout period.

Then the study was repeated with the comparing

drug in the same manner on day 15 through day 24.

Overall study period was 24 days.

The patients were assessed at pain clinic on

day 1 (screening and randomization visit), days 15

and 25. They were contacted by phone by one of

the researchers following a dose adjustment to

assess compliance, tolerability and pain diary

completion. Telephone contact was done on the

day 2, 4, 8, 16, 18 and 22. Previous adjuvant

analgesics were unchanged throughout the study

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period. Demographic data, primary tumor site,

Palliative Performance Scale, oral morphine daily

equivalent dose and side effects, concomitant pain

medication, pain on average in the last 24 hours at

the screening visit, right now pain, and best and

worst pain scores in the last 24 hours were

recorded.

Patients could be withdrawn from the trial at

any time of the study. Any other analgesics apart

from MSS were not allowed during the study

period. The patient was withdrawn if there were ≥

grade 3 adverse events on CTCAE version 4.0,

patients needed more than three daily p.r.n. MSS

doses, extreme unexpected events such as gut

obstruction, brain metastasis, unable to take

oral medication, bone fractures, chemotherapy,

radiotherapy, bisphosphonate therapy or surgery

during the treatment phase for disease control, and

finally, noncompliance: missing ≥ 2 consecutive

days of study medication or less than 80% study

medication.

Primary outcome of the study was to

determine the analgesic efficacy. The primary

efficacy was defined as the average pain score

reduction between day 1 and day 8 of each study

period. Secondary outcome comparisons were

percentage of patients who had pain intensity at

least 3 points average pain score reduction for

follow-up days, amount of rescue MSS for

breakthrough pain, and incidence of side effects

such as sedation, dizziness, nausea, vomiting and

constipation.

Statistical Methods A sample size was determined from a

minimum difference of mean pain score reduction

between the two groups equaled to two16, assumed

that standard deviation (SD) was 2.5. The power

was 80% and two - tailed α was 0.05. Calculation

resulted in 26 patients per group. To compensate

for 20% attrition rate, we included 32 patients.

Analysis of the analgesic efficacy was performed

by an analysis of covariance (ANCOVA). Intention -

to - treat (ITT) basis was used for the main

analysis. The percentage of patients achieving

average pain score reduction at least 3 was plotted

by day.

Chi - square test was used to analyze safety

data using ITT basis. Statistically significance was

when p < 0.05.

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Figure 1 Study protocol flow chart

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Figure 2 Protocol flowchart and follow up

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Figure 3 Enrollment of study participants.

Results Patient enrollment

In Figure 3, thirty - two patients were eligible

and randomly assigned; 30 in gabapentin and 26 in

placebo group. Two patients in gabapentin group

were excluded because one had chemotherapy

during period B and another one had radiation

in period A. Six patients in placebo group were

excluded; period B chemotherapy 1, period B

pamidronate 1, period A radiation 1, period B

radiation 1, period B loss to follow up 2. Finally,

30 patients in gabapentin group and 26 in the

placebo group completed the 24 - day study protocol.

Patient Demographic and Baseline Clinical

Characteristics

Demographic and baseline pain characteristics

of the patients are shown in Table 1. Both groups

were comparable in age, sex, primary tumor site,

metastatic bone lesion as the major pain, Palliative

Performance Scale, stabilized oral morphine daily

equivalent in mg and side effects, concomitant pain

medication, average pain score in the last 24 hours,

right now pain, best pain scores in the last 24 hours

and worst pain scores in the last 24 hours. The

majority of patients had anticonvulsant analgesic

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include gabapentin <900 mg/day and pregabalin

<150 mg/day before recruitment. The demographic

characteristics of patients were comparable.

Table 1 Demographic characteristics of the patients

Gabapentin (n = 30) Placebo (n = 26) p - value

Age, year (mean±SD)

Sex, n (%)

Male

Female

Primary tumor site, n (%)

Lung

Breast

Hepatobiliary

Colon-rectum

Head & neck

Gynecological

Urological

Unknown

Others

Metastatic bone lesion as the major pain, n (%)

Spine

Long bone/extremities

Pelvis

Rib, clavicle

Chest wall

Palliative Performance Scale, n (%)

20

30

40

50

60

70

80

55.07±12.60

9(30.0)

21(70.0)

5(16.7)

8(26.7)

2(6.7)

2(6.7)

2(6.7)

6(20.0)

2(6.7)

3(10.0)

13(43.3)

4(13.3)

7(23.3)

1(3.3)

5(16.7)

0

1(3.3)

3(10.0)

7(23.3)

7(23.3)

10(3.3)

2(6.7)

55.54±12.80

6(23.1)

20(76.9)

5(19.2)

8(30.8)

1(3.8)

2(7.7)

2(7.7)

5(19.2)

1(3.8)

2(7.7)

11(42.3)

4(15.4)

7(26.9)

0

4(15.4)

0

1(3.8)

3(11.5)

5(19.2)

6(23.1)

9(34.6)

2(7.7)

0.890

0.560

>0.999

0.910

>0.999

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Gabapentin (n = 30) Placebo (n = 26) p - value

Palliative Performance Scale, median(range)

Oral morphine daily equivalent, mg

median (range)

Concomitant pain medication, n (%)

NSAIDs

Antidepressant

Anticonvulsant

Bisphosphonates

Pain characteristics at recruitment, (mean±SD)

Average pain score in the last 24 hours

Right now pain

Best pain scores in the last 24 hours

Worst pain scores in the last 24 hours

Untoward symptoms at beginning of the study,

n (%)

Somnolence

Dizziness

Nausea

Vomiting

Constipation

60(80-30)

60(120-20)

0

2(6.7)

4(13.3)

0

5(10-4)

5(10-3)

3(7-0)

9(10-3)

1(3.3)

3(10.0)

1(3.3)

0

15(51.7)

60(80-30)

60(120-20)

0

1(3.8)

4(15.4)

0

5(4-9)

6(4-10)

3(7-2)

8.5(10-5)

5(19.2)

4(15.4)

0

0

11(42.3)

0.899

0.719

-

>0.999

>0.999

-

0.946

0.086

0.638

0.928

0.055

0.543

0.348

-

0.485

*p-value <0.05

Primary Efficacy Outcome

The average pain score reduction between

day 1 and day 8 of each period of the study for

gabapentin and placebo groups were similar, 2.77 ±

2.10 and 2.46 ± 1.25, p = 0.533. Mean average pain

in the last 24 hours, right now pain, best and worst

pain scores in the last 24 hours for two treatment

groups were also comparable (Table 2). Repeated

measures ANOVA indicated that there was no

significant time effect between the groups.

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Table 2 Pain Scores during treatment period (Day 3 - 8)

Pain characteristics, (mean ± SD) Gabapentin (n = 30) Placebo (n = 26) p - value

Average pain score in the last 24 hours

Right now pain

Best pain scores in the last 24 hours

Worst pain scores in the last 24 hours

3.34±1.22

3.62±1.04

2.61±0.88

5.56±1.71

3.40±1.07

3.78±1.27

2.51±0.92

5.54±1.86

0.865

0.615

0.699

0.971

Secondary Efficacy Outcomes

Percentage of patients who had average pain

score reduction at least 3 points for follow - up

days per patient was not different between the

groups (Figure 4). The average percentage of

follow - up days per patient (day 3 - 8) with

average pain score reduction ≥ 3 are 53.23 ± 2.81

in the gabapentin group and vs 47.44 ± 3.53 in

the placebo group, p = 0.586. The use of rescue

analgesic was not different. Average doses of MSS

in gabapentin and placebo group were similar; 9.25

± 7.77 mg/patient vs 11.73 ± 11.62 mg/patient,

respectively, p = 0.607. No patients in both groups

discontinued the treatment due to adverse events.

Figure 4 Percentage of patients with average pain score reduction ≥ 3 from baseline at each study day

No statistically significant difference between the two groups

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Table 3 Incidence of adverse events during treatment period (day 3 - 8)

Side effect Gabapentin (n = 30) Placebo (n = 26) p - value

Somnolence, n (%)

Grade 1

Grade 2

Grade 3

Dizziness, n (%)

Grade 1

Grade 2

Grade 3

Nausea, n (%)

Grade 1

Grade 2

Grade 3

Vomiting, n (%)

Grade 1

Grade 2

Grade 3

Constipation, n (%)

Grade 1

Grade 2

Grade 3

24(82.76)

8(27.59)

1(3.45)

27 (90.00)

4(13.33)

0

30(100)

2(6.67)

0

30(100)

1(3.30)

1(3.30)

19(63.30)

11(36.67)

0

20(76.92)

11(42.31)

2(7.69)

21(80.77)

7(23.33)

2(7.69)

26(100)

6(23.08)

0

26(100)

2(7.69)

1(3.85)

16(61.54)

11(42.31)

2(7.69)

0.780

0.218

0.470

0.325

0.202

0.122

-

0.080

-

-

0.470

0.918

0.890

0.666

0.122

Grading of severity of every adverse event are classified as followed

Grade 1 - Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not

indicate

Grade 2 - Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate

instrumental ADL

Grade 3 - Severe or medically significant but not immediately life-threatening; hospitalization or

prolongation of hospitalization indicated; disabling; limiting self-care ADL

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Discussion Mechanisms of metastatic bone pain include

both neuropathic and nociceptive. Previous study

showed that 17% of patients (95% CI, 10% to

24%) had positive Self-Reported Leeds Assessment

of Neuropathic Symptoms and Signs scores,

indicating that metastatic bone pain might be

neuropathic. Moreover, these patients had higher

brief pain inventory worst pain score than patients

without neuropathic characters (8.3 vs 7.0,

respectively; P = 0.016).17 This findings explain

refractory outcome of opioid treatment of bone

pain. Moderate-to-high doses of opioids may be

required to achieve pain control in metastatic bone

pain. Opioids have significant dose-limiting side

effects. Hoping that gabapentin in adequate dose

for the relief of neuropathic pain may accentuate

opioid analgesic effects thereby reduces the

untoward incidence; gabapentin is usually added

into treatment regimen.

There is also a randomized controlled study

of pregabalin; a gabapentinoid, in patients with

metastatic bone pain indicated that pregabalin use

may reduce metastatic bone pain10. Unfortunately,

the study was terminated early because of difficulty

in patient recruitment and big sample size required

causing delayed in the study timing. However, the

preliminary results showed that mean change ± SD

of NRS worst pain in pregabalin vs placebo groups

were 1.53 ± 1.81 vs 1.23 ± 1.74. The NRS average

pain in pregabalin vs placebo group were 1.24 ±

1.65 vs 0.85 ± 1.59. But more patients in pregabalin

group reported reductions in pain compared with

placebo group both for 30% and 50%.

Gabapentin, another α2 δ1 N-type calcium

channel may exert either the same or different

effect. It has analgesic effect in several clinical

trials of nonmalignant chronic neuropathic pain

and adjuvant treatment for cancer pain with

a neuropathic component in combination with

opioid analgesics. But there is still no conformed

evidence.

This study required patients with a stable

disease period and no plan for chemotherapy or

radiotherapy. The results of this study showed no

difference in average pain score reduction ≥ 3 from

baseline between the groups. The reason could be

due to: (1) Most of the participants had moderate

pain score before entering the study, not severe

pain. (2) We used cut-off value the absolute pain

score reduction follow-up period ≥ 3 to determine

significant difference. If we had used cut-off value

the pain score reduction follow-up period at least

216, the outcome might have been more approach

to significant difference. In Figure 4, average

percentage of patients with average pain score

reduction ≥ 3 at each study day tends to be higher

in the gabapentin group (53.23 ± 2.81 %) than in

the placebo group (47.44 ± 3.53), p = 0.586, even

though it is not significant. In addition, peak of

percentage of patients with average pain score

reduction ≥ 3 was at the study day 7 - 9. Therefore,

if gabapentin was used further, it might be possible

to find discrepancy of the result. Side effects of

gabapentin treatment group were mild in most

cases and not different from placebo.

Gabapentin is usually added into pain

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management regimen. It is difficult to find any

patient who did not have it before recruitment. So

we excluded ones who got gabapentin ≥ 900 mg/

day or pregabalin ≥ 150 mg/day but for ones who

had less than aforementioned doses could be

included. Nevertheless, these doses were decreased

20-30% daily until completely stop in 4 days. By

that time opioid doses were adjusted to control

pain. Four days is the effective period of wash out

the drug because it is 5 times the half-life of

gabapentinoids. In our plan, patient who consumed

more than three daily p.r.n. MSS doses would be

withdrawn because it might indicate progression of

the disease and basal opioid dose should be

escalated. Fortunately, there was no such patient in

the study.

This study is the first well controlled study

to prove benefit of adding gabapentin to opioid

analgesia in metastatic bone pain patients. We

conducted crossover design in order to remove

patient variability and increasing precision of

estimation. However, there are some limitations.

Recruitment of cancer patients in clinical trials is

difficult. It is unethical to withhold all other

concomitant treatments such as radiotherapy,

chemotherapy, analgesic adjuvants and surgery

because they are usually needed for controlling of

the disease. The second limitation is that our

patients are only the ones with moderate pain.

Participants who had severe pain might want

radiation or chemotherapy for the disease and pain

control. Furthermore, we had to wait for at least

one month after radiation and two weeks after

chemotherapy before recruitment, otherwise there

might have carry over effect which would confound

the drug effects. Finally, after randomization,

changing in cancer treatment plan such as

chemotherapy, radiation, bisphosphonate therapy

led to dropping out.

The result is that gabapentin did not

accentuate analgesic efficacy of opioid in metastatic

bone pain. There may be a significant change in the

study result if (1) the study duration is extended;

(2) using a cut-off value of pain score reduction in

follow-up period at least 2 or pain intensity

difference was 33%. Suggestion for further study is

to use varied gabapentin dosage in order to achieve

an optimal dose. Nevertheless, as gabapentin is

usually safe and has wide therapeutic index, adding

gabapentin to opioid analgesic dose not add risk,

especially when there is an indication of adjuvant

treatment for cancer pain such as neuropathic pain

component.

Conclusion Adding gabapentin to opioid analgesic dose

not accentuate efficacy of pain relief by opioids in

metastatic bone pain patients.

Acknowledgement The authors are grateful for the “Prasert

Prasarttong - Osoth fund” via Thai Medical

Association. Thanks to Research Support Group,

Department of Anesthesiology, Faculty of Medicine

Ramathibodi Hospital.

None of the authors has conflict of interes

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Reference 1. Coleman RE, Rubens RD. The clinical course

of bone metastases from breast cancer. Br J

Cancer. 1987;55:61-6.

2. Buga S, Sarria JE. The management of pain in

metastatic bone disease. Cancer Control.

2012;19:154-66.

3. Smith HS. Painful boney metastases. Ann

Palliat Med. 2012;1(1):14-31.

4. Rustøen T, Moum T, Padilla G, Paul S,

Miaskowski C. Predictors of quality of life in

oncology outpatients with pain from bone

metastasis. J Pain Symptom Manage. 2005;

30:234-42.

5. Bruera E, Kim HN. Cancer pain. JAMA.

2003;290:2476-9.

6. Hanks GW. The pharmacological treatment of

bone pain. Cancer Surv. 1988;7:87-101.

7. Coleman RE. Management of bone metastases.

Oncologist. 2000;5:463-70.

8. Peters CM, Ghilardi JR, Keyser CP, Kubota K,

Lindsay TH, Luger NM, et al. Tumor-induced

injury of primary afferent sensory nerve fibers

in bone cancer pain. Exp Neurol. 2005;193:

85-100.

9. Ballantyne JC, Cousins MJ, Giamberardino

MA, McGrath PA, Rajagopal MR, Smith MT,

et al. Pain clinical update; bone cancer pain.

Pain Clinical Update. 2009;17:1-6.

10. Sjo¨lund KF, Yang R, Lee KH, Resnick M.

Randomized study of pregabalin in patients

with cancer-induced bone pain. Pain Ther.

2013; 2: 37-48.

11. Caraceni A, Zecca E, Bonezzi C, Arcuri E,

Tur RY, Maltoni M, et al. Gabapentin for

neuropathic cancer pain: A randomized

controlled trial from the gabapentin cancer pain

study group. J Clin Oncol. 2004;22:2909-17.

12. Donovan-Rodriguez T, Dickenson AH, Urch

CE. Gabapentin normalizes spinal neuronal

responses that correlate with behavior in a rat

model of cancer-induced bone pain. Anesthesiology.

2005;102:132-40.

13. Chewaskulyong B, Sapinun L, Downing GM,

Intaratat P, Lesperance M, Leautrakul S, et al.

Reliability and validity of the Thai translation

(Thai PPS adult Suandok) of the palliative

performance scale (PPSv2). Palliat Med.

2012;26(8):1034-41.

14. National Institutes of Health National Cancer

Institute, Department of Health and Human

Services. Common terminology criteria for

adverse events (CTCAE) version 4.0, 2009-

2010. United States:2009.

15. Serafini AN. Therapy of metastatic bone pain.

The J Nucl Med. 2001;72(6):895-906.

16. Farrara JT, Portenoy RK, Berlina JA, Kinmana

JL, Stroma BL. Defining the clinically important

difference in pain outcome measures. Pain.

2000;88:287-94.

17. Kerba M, Wu J, Duan Q, Hagen NA, Bennett

MI. Neuropathic pain features in patients with

bone metastases referred for palliative radio-

therapy. J Clin Oncol. 2010;28:4892-97.

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ผลของ Gabapentin เสริมกับ Opioids ในการระงับปวดจากมะเร็งแพร่กระจายมากระดูก การศึกษาแบบไขว้กัน

บทคัดย่อ

ที่มาและเหตุผล: มะเร็งแพร่กระจายมายังกระดูกมักทำให้ผู้ป่วยมีความปวดรุนแรง ซึ่งการระงับปวด

ด้วยยากลุ่มโอปิออยด์อาจไม่พียงพอ หรือมีฤทธิ์ข้างเคียงที่ทำให้ผู้ป่วยไม่สบายมากขึ้น ผู้เชี่ยวชาญจึงแนะนำ

ให้ใช้ยาเสริม อย่างไรก็ตามมักมีผู้นิยมใช้ยากาบาเพ็นตินอยด์ซึ่งเป็นยาระงับปวดประสาท แม้ว่าจะไม่เป็นที่

แน่ชัดว่ายากลุ่มนี้มีประโยชน์จริงสำหรับปวดจากมะเร็งแพร่กระจายมายังกระดูก วัตถุประสงค์: เพื่อศึกษา

ประสิทธิภาพการระงับปวดและผลข้างเคียงของยา gabapentin 900 mg/วัน ที่ให้ร่วมกับยา opioids ในการ

ระงับปวดจากภาวะมะเร็งแพร่กระจายมากระดูกที่มีความปวดระดับปานกลางถึงปวดมาก วิธีการศึกษา:

เป็นการศึกษาแบบไขว้โดยมีกลุ่มควบคุมและสุ่มผู้ป่วย โดยใช้ขนาดยาคงที่ ศึกษาในผู้ป่วยที่มีภาวะมะเร็งแพร่

กระจายมากระดูกจำนวน 32 คน ทุกรายได้รับยาโอปิออย์จนกระทั่งขนาดยาคงที่ แบ่งผู้ป่วยเป็น 2 กลุ่ม คือ

กลุ่ม gabapentin และ placebo โดยการสุ่ม, กลุ่มละ 16 คน แต่ละกลุ่มได้รับยา 2 ช่วง ช่วงละ 10 วัน ระยะพัก

4 วัน แล้วสลับยาที่ศึกษาในขนาดและวิธีเดียวกัน กลุ่มศึกษาได้รับกาบาเพ็นติน 900 มก/วัน กลุ่มควบคุมได้

รับยาหลอก รวมเวลาศึกษาทั้งสิ้น 24 วัน ประเมินว่าผู้ป่วยได้รับยาตามแผนการวิจัยและปัญหาที่เกิดจากยา

โดยทางโทรศัพท์ในวันที่ 2, 4, 8, 16, 18 และ 22 ประเมินที่ห้องตรวจในโรงพยาบาลวันที่ 1, 15, และ 25 สิ่งที่

ประเมินคือ ค่าเฉลี่ยคะแนนปวดที่ลดลงในวันที่ 1 เทียบกับ 8 ของแต่ละช่วงการศึกษา, ร้อยละของผู้ป่วยที่มี

คะแนนปวดเฉลี่ยที่ลดลง >3 จำนวนยาโอปิออย์ที่ผู้ป่วยต้องรับเสริม และภาวะแทรกซ้อน ผลการศึกษา:

ผู้ป่วย 30 รายได้รับกาบาเพ็นติน และ 26 รายได้รับยาหลอก ค่าเฉลี่ยคะแนนปวดที่ลดลงของทั้งสองกลุ่ม

ไม่ต่างกันอย่างมีนัยสำคัญทางสถิติ กลุ่มกาบาเพ็นติน 2.77 ± 2.10 และกลุ่มยาหลอก 2.46 ± 1.25, (p = 0.533)

ผู้ป่วยที่มีค่าเฉลี่ยคะแนนปวดที่ลดลง > 3 ร้อยละ 53.23 ± 2.81 และ 47.44 ± 3.53), p = 0.586 ปริมาณ

ยาแก้ปวดเสริมไม่ต่างกัน p = 0.607 ภาวะแทรกซ้อนต่างๆได้แก่ ง่วง มึนงง คลื่นไส้อาเจียน และท้องผูก

ไม่ต่างกัน

สรุป: การใช้กาบาเพ็นตินเสริมไม่ได้เพิ่มผลระงับปวดจากโอปิออยด์ในผู้ป่วยปวดจากภาวะมะเร็งแพร่กระจาย

มากระดูก

คำสำคัญ: กาบาเพ็นติน ภาวะมะเร็งแพร่กระจายมากระดูก ปวดกระดูก โอปิออยด์

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