Era's Lucknow Medical College And Hospital
PAIN MANAGEMENT BY WHO STEP LADDER PATTERN PROTOCOL IN CASES OF CERVICAL CANCER
ABSTRACT
To assess pain in cases of cancer cervix and to evaluate the
response to pain management according to WHO step ladder pattern in cases of
cancer cervix, total 209 carcinoma cervix diagnosed and admitted case were
recruited in the study. Baseline pain score was measured for each patient. For
mild to moderate pain (VAS ≤ 7) , step 1 analgesic, NSAID, diclofenac sodium
(50 mg TDS) was prescribed. Pain scores were reevaluated after 48 hrs and
change of score was recorded. If pain persisted (same score), worsened (score
increased) or score decreased but with a VAS score of > 4 , case was
considered as non responder and patient was switched to step 2
analgesic.
Step 2 was also applied directly to patients presenting with severe pain ( VAS
>7) at the time of recruitment. Drugs used in step 2 was oral tramadol (50
mg QID ) along with Diclofenac ( 50 mg TDS) . VAS Score was reevaluated after
48 hrs. If score still remained above 4; adjuvant analgesics (Amitryptiline
25-75 mg OD, Prednisolone 5mg BD – 10 mg/day) were added to step 2. Step 2 non
responders were treated with step3 protocol. In step 3, tab morphine (10 mg BD
upto maximum 30 mg BD) was given after stopping all other drugs . After 48 hrs,
scores were re evaluated; if scores remained >4; adjuvant analgesics (
Amitryptiline 25-75 mg OD, Prednisolone 5mg BD – 10 mg/day ) were added. After
48 hrs if still pain scores did not decrease to <4, case was declared as
failure . The WHO algorithm was followed as per the response of the patients.
Outcome showed decrease in pain score using Visual Analogue Scale Score. 209
patients were enrolled in the study. 60 patients had no pain at baseline. Out
of 149 patients with pain, 44.9 % (67) patients achieved complete pain relief
at step 1. Out of the remaining 82 patients , 5 were lost to follow up. 49.3 %
(38) achieved complete relief at step 2 . Only 39 patients did not reach score
of zero after step 2 but 35 (89.7%) out of them achieved complete relief after
step 3. Out of 142 patients ( excluding lost to follow up ), 2 cases were
declared as failure. Among these failure cases, one of them had metastasis of
femur and symphysis pubis; bisphosphonates were started. Other patients had
bladder and bowel involvement diagnosed on repeat cystoscopy. This WHO
guideline implementation study supports use of algorithm in decision making for
cancer pain management. Following the same we were able to achieve effective pain
relief in 96% of our patients with failure rate of only 4%. It further helped
to reduce patient’s agony and improved the quality of life.
Key Words: Cancer
cervix , Pain , Treatment.
INTRoDUCTIoN occurs from many causes like somatic, visceral,
neuropathic and bone pain ( Ashby 1992 ) . Ninety percent of pain in
Pain is
a subjective multidimensional experience unique to cancer cervix is a complex
resulting from the tumor itself, an individual, with a potential impact on
function, status and in which 70% of pain develops from tumor invading or
quality of life. Yet it is one of the most common unattended compressing
uterosacral ligament and sacral plexus, and 20% and unsolved problem for cancer
patients. Cancer cervix of cancer pain is related with its treatment (
radiation and is one of the leading cause of cancer death among women
chemotherapy related neurotoxicity). Rest 10% of pain is due worldwide.
Incidence of new cancer patients in India is about to unrelated illness. Common
sites of pain in cancer cervix 100,000 per year and 70% or more of these are
stage 3 or are back, lower abdomen, flank, buttocks and perineum.
higher
at the time of diagnosis (Venugopal T C 1995). Pain Pain can be pressure like,
dull aching , burning , cramping or is a debilitating symptom associated with
cancer cervix. It lancinating (Saphner 1989).
occurs in 25-50% patients with newly diagnosed malignancy,
in more
than 75% of those with advanced disease, and in WHO recommended a stepladder
pattern algorithm as a 33% of those undergoing treatment (Van den Beuken 2007)
. guideline for pharmacological management of cancer pain in Pain in patients
with cancer cervix is a complex process that 1986 ( WHO 1996 ) which was updated
in 1996. It describes three step progression from the use of nonopoid
medication (acetaminophen, dipyrone, NSAIDs) to weaker opoids (codeine,
dextropropoxyphene , tramadol) and then strong opioids ( morphine, methadone,
oxycodone, hydromorphone, buprenorphine ) depending on pain intensity. Using
this, pain control can be achieved in 85% of patients. The use of guidelines
has been studied in over 30,000 patients, proving its usefulness and efficacy (
Zech 1995 ). However, despite the availability of effective guidelines for pain
control, most cancer patients have a poor quality of life which increases their
agony. Effective pain management improves quality of life as well as the
ability to tolerate diagnostic and therapeutic procedures (Blanchard 1986). Henceforth,
this study was done to assess the need of pain management in cancer cervix and
to evaluate the efficacy of pain management by WHO stepladder pattern in the
patients of cancer cervix.
MATERIAlS AND METHoDS
This pilot prospective cohort study was conducted in the
Department of Obstetrics and Gynaecology, in collaboration with Department of
Anaesthesia, KGMU , over a period of one year. Total 209 patients were
diagnosed as carcinoma cervix, admitted in the Department of Obstetrics and
Gynaecology were recruited in the study. These patients were either receiving
or were planned for chemoradiation. Patients with systemic debilitating
diseases (renal failure, Diabetes Mellitus, HIV, respiratory and hepatobilliary
diseases), peptic ulcer, bleeding diathesis , thrombocytopenia, epilepsy or
history of seizures and patients who underwent major surgery within 2 weeks
were excluded. Written informed consent was taken from each patient before pain
assessment and management. Demographic details and complete history was
recorded. General, systemic and gynaecological examination was done. Variables
recorded were age, parity, presenting complaints, stage of disease, delay in
start of treatment, uterosacral ligament involvement, radiotherapy, anaemia,
smoking/ tobacco, poor family support.
PAIN
ASSESSMENT
Initial
pain assessment was done by taking detailed pain history regarding pain
characteristics like intensity, location, quality, duration and temporal
pattern. Pain intensity was measured by visual analogue scale.VAS is a
graduated line 100 mm in length , anchored by word descriptors at each end like
no pain and worst pain. The patient marks on the line the point that they feel,
represents their perception of their current state. The VAS score is determined
by measuring in millimeters from the left end of the line to the point that the
patient marks. According to VAS score pain was categorized into mild, moderate
and severe categories. Patients with mild pain, have VAS score in the range of
1-4, those having moderate pain have VAS score, in the range of 5-6 and
patients having severe pain have VAS score ≥ 7. Subsequent assessment was done
after giving the drug , at regular intervals and at each new report of pain. It
was done 24-48 hours after oral administration.
PAIN
MANAGEMENT
Oral route was preferred with a fixed schedule dosing to manage
constant pain and prevent pain from worsening. Rescue (breakthrough) dose was
combined with regular fixed schedule analgesics to control episodic exacerbation.
Baseline pain scores were measured for each patient. For mild to moderate pain
(VAS ≤ 7) , step 1 analgesic, NSAID, diclofenac sodium (50 mg TDS) was
prescribed. Pain scores were reevaluated after 48 hrs and change of score was
recorded. If pain persisted (same score), worsened (score increased) or score
decreased but with a VAS score of > 4 , case was considered as non
-responder and patient was switched to step 2 analgesic. Step 2 was also
applied directly to patients presenting with severe pain ( VAS >7) at time
of recruitment. Drugs used in step 2 was oral Tramadol (50 mg QID ) along with
Diclofenac ( 50 mg TDS) . VAS Score was reevaluated after 48 hrs. If
score still remained above 4; adjuvant analgesics (Amitryptiline 25-75mg OD,
Prednisolone 5mg BD – 10 mg/ day ) were added to step 2. Step 2 non -
responders were treated with step3 protocol. In step 3, tab Morphine (10 mg BD
upto maximum 30 mg BD) was given after stopping all other drugs. After 48 hrs,
scores were reevaluated; if scores remained >4; adjuvant analgesics
(Amitryptiline 25-75 mg OD, Prednisolone 5mg BD – 10 mg/day) were added. After
48 hrs if still pain scores did not decrease to <4, case was declared as
failure as per study protocol and some other palliative measures (neurolytic sympathetic
plexus block, epidural block, epidural neurolysis) was applied to relieve pain.
Once the patient’s pain score declined to 0; she was followed up to 2 weeks so
as to check any increase in pain. At each step of the ladder, adjuvant drugs
(laxatives/stool softeners ,antiemetic) were considered in selected patients to
treat concurrent symptoms (Mercadante 2001).
STATISTICAl
ToolS
Was done using SPSS (Statistical Package for Social Sciences)
version 15.0 statistical analysis software
RESUlTS
A total
209 patients of carcinoma cervix were enrolled in the study. The mean age of
patients in this study was 49.7 yrs and maximum patients were in the age group
41-50 years (48%). Majority of the subjects were multiparous (67.5%), residing
in rural areas (80.3%), of low socioeconomic status (80%) and illiterate (85%)
. Most common presenting symptoms were discharge per vaginum (75%), pain (61%),
postmenopausal bleeding ( 44%) , post coital bleeding (15.7%), bladder and
rectal symptoms (10%). Most common type of pain was low backache (70%) followed
by lower abdominal pain (52%) and perineal pain (34.6%). Majority of patients
had pressure like continuous aching pain (74%) with the duration of onset of
pain being < 6 month in most of the patients. After pain assessment of 209
patients, 149 were found eligible for pain management as per WHO step ladder
pattern and their response was analysed Out of 149 patients with pain, 44.9 %
(67)
patient achieved complete pain relief at step 1. Out of the remaining 82
patients , 5 were lost to follow up. 49.3 %
(38) achieved complete relief at
step 2 , however 5 patients also required adjuvant medication along with step
2. Only 39 patients did not reach score of zero after step 2 but 35 (89.7%) out
of them achieved complete relief after step 3. Out of 142 patients (excluding
lost to follow up), 2 cases were declared as failure. Among these failure
cases, one of them had metastasis of femur and symphysis pubis; bisphosphonates
were started. Other patient had bladder and bowel involvement diagnosed on
repeat cystoscopy.
Association between involvement of uterosacral ligament and step
of pain relief was analysed using chi square test. Uterosacral ligament
involvement was associated with higher step of pain relief (p<0.0001). In
93% of patients with uterosacral involvement, no pain relief was seen at step
1.Other factors like presence of anaemia, addiction, delay in start of
treatment, post radiotherapy, poor family support , old age , illiteracy , low
socioeconomic status were studied using logistic regression analysis. These
factors did show an increased risk ratio but were not statistically
significant. Side effects were observed in all analgesic group of patients,
more commonly with Morphine (30.2%) and Tramadol
Table 1 : Correlation
between stage of the disease and severity of pain
Stage No. Pain No Pain
mild Moderate Severe
1 24 7 (29.2%) 17(70.8%)
4 2 1 2 88 57(64.8%) 31(35.2%) 6 42 9 3 90 78(86.7%) 12(13.3%) 8 29 41 4 7
7(100%) 0 ( 0%) 0 0 7 Total 209 149 60 18 73 58
RESPoNDERS 18 72 57 NoN RESPoNDERS 0 1 1
1. Stage
Vs Pain: χ2=35.850
(df=3); p<0.001
Table 2 : Correlation between
initial pain scores and response to step ladder therapy
Step VAS No. Responders Non lost to Response to
Responders follow up adjuvants
1 1-6 91 67 (73.6%)
24 -2 >=7 58 17(29.3%) 41 -2 nonresponders of step1 24 16/23 (69.6%) 7/23
(30.4%) 1
2 direct
+ nonresponders of 81 33/81(40.7%) 48/81 (59.3%) -step1 2+adjuvants
nonresponders of step 2 48 5 39 4 5/44(11.4%) 3 nonresponders of step 2 39 35
(89.7%) 4 (10.3%) 3+adjuvants nonresponders of step 3 4 2 2 -2/4(50%)
Table 3 : Correlation between stage of disease and response to
pain , the proportion of responders decreased from stage 1 to stage 4 showing a
statistically significant inverse
Table 4 : Correlation between stage of the disease and step of
pain relief
STAGE STEP
1 STEP 2 STEP 3FAIlED ( n= 67) (n = 38) ( n = 37) ( n= 2)
1 ( n= 7) 6/7
(85.7%) 1 /7 (14.3%) 0 0 2 (n=57) 43/57 ( 75.4%) 14/57 (24.6%) 0 0 3 (n=75)
18/75 (24 %) 23/75 ( 30.7%) 33/75 (44%) 1/75 (1.3%) 4 (n=5) – 0/5 (0%) 4/5
(80%) 1/5 (20 %)
Table 5 : Shows an
inverse association between response rate and initial pain category
(p<0.001)
INITIAl PAIN SCoRE
RESPoNDERS NoN
RESPoNDERS
1-4 18 0 5-6 72 1 >=7 52 1 + 5 ( lost to
follow up )
χ2=6.824 (df=2); p<0.001
Chi square test ‘p’ value = 0.0001
(25%) compared from
Diclofenac, constipation was more commonly seen with Morphine (25.6%) compared
from Tramadol (8.5%). Epigastric pain was observed only in Diclofenac group
(10.9%). Physical dependence, tolerance and addiction was not seen.
DISCUSSIoN
Van
den Beuken (2007), in a review showed that prevalence of pain was 50% in
all cancer stages, 64% in patients with metastatic or advanced stage disease,
59% in patients on anticancer treatment and 33% in patients after curative treatment.
In the present study, 71.3 % patients had pain as the presenting complaint and
majority of the patients (57%) with pain were in advanced stage (3 and 4)
followed by 38.2 % in stage 2 and 4.6 % in stage 1 of cancer cervix. Thus,
incidence of pain increasing with stage of the disease. Pain evaluation in the
present study was done using Visual analogue scale (Wewers 1990). Various other
methods of pain measurement are Edmonton symptom assessment (Bruera 1991),
Wisconsin Brief pain inventory (Cleeland 1994), Memorial pain assessment card
(Fishman 1987), McGill pain questionnaire (Melzac 1987), Hopkins pain rating
instrument (Grossman 1992), Simple descriptive scale (McGrath 1998), Numeric
pain distress scale and Facial scale. The goal of initial assessment of pain is
to characterize the pathophysiology of pain and to determine the intensity of
pain and patients ability to function.
Ventafridda
V etal (1990), in a study found NSAIDs effective and relatively well tolerated
in treatment of cancer pain. McNicol E etal (2004) found that nonsteroidal
anti-inflammatory drugs were preferred for mild to moderate cancer pain. Pain
intensity increases with advancing stage due to involvement of ureters, pelvic
wall or sciatic nerve routes. This was confirmed with findings of this study
since the severity of pain increased (p<0.001) with stage of disease.
Radbruch
L etal (1996) found that Tramadol is safe and effective in the treatment of
mild to moderate cancer pain when used in combination with non opoids In
present study, Step 1 response rate was 73.6%. However, among patients directly
recruited for step 2 the response rate was only 29.3%, showing a statistically
significant difference (p<0.001). This indicates that among patients
directly recruited for step 2, the protocol does not seem to be a good-fit.
Among patients recruited to step 2, after failure of step 1, the response rate
was 69.6% which was at par with the response rate at step 1 (73.6%) (p=0.696).
This indicates the appropriateness of protocol. Overall response among patients
recruited to step 2 (both directly recruited and those promoted to step 2 after
failure of step 1) was 40.7% which is significantly lower as compared to that
for step 1 (p<0.001). As highlighted above, this difference in response of two
steps was owing to low response rate observed amongst directly recruited
subjects of Step 2.
Response
to step 3 (89.7%) was significantly higher as compared to both steps 1 and 2,
thereby indicating its utility as the terminal, final step of the protocol.
40.7 % of severe pain patients responded to Tramadol and 89.7 % of severe pain
patients responded to morphine. Thus, Morphine was found to be more effective
drug in (p<0.001) for severe pain. Gatti A et al (2009) found that with
Morphine therapy 30 -60 mg / day VAS score reduced significantly. They
concluded that Morphine therapy could be implemented as a standard therapy to
manage moderate to severe chronic pain in cancer patients. Grond S. etal (1999)
compared the efficacy and safety of high dose Tramadol and low dose Morphine
for mild to moderate cancer pain and observed high dose Tramadol is equally
effective and safe for mild to moderate cancer pain as low dose Morphine.
Wilder Smith etal (1994) observed that for strong cancer pain Morphine is more effective
than Tramadol.
Pain
intensity at initial assessment is a significant predictor of response rate in
pain management amongst cancer patients. We observed that as the initial VAS
score increased, the response rate decreased (p<0.001). Robin et al (2009)
in a study found that pain with moderate to severe intensity required
significantly higher opioid doses and more adjuvant modalities.
Guay D R (2001)
evaluated the analgesic benefits of tricyclic antidepressants in cancer
patients. Wooldridge J E etal (2001)
Table 6 : Shows comparison of response at various steps of
treatment
in a study reported that
anti-inflammatory component of corticosteroid plays role to relieve pain in
cancer cervix. The response to adjuvants was 11.4% only which was significantly
lower compared to that of step 2 (p<0.001), thus indicating minimal role of
adjuvant drugs that this step could be skipped for the next step. Yet, adjuvant
drugs were found to be valuable for patients who did not respond to step 2 or
step 3 alone, 11.4% in step 2 and 50% in step 3 responded well after addition
of adjuvant drugs.
In
the present study, 95.3% patients of cancer cervix with pain, responded to WHO
guided pain management protocol. Grand etal (1993) reported that WHO guided
pain management protocol provided adequate analgesia in 95% of patients with
camcer pain. Gayatri Palat etal (1993) in a study reported that pain in cancer
cervix patients could be managed effectively in about 80-90% of patients. C S
Cleeland et al (2005), in an inter group study , coordinated by Eastern
cooperative oncology group, registered 225 patients of cancer pain. 43% were
given milder opiod (codeine) and 24% received stronger opiod (morphine). they
reported 66% relief provided by medication. Of 4 non-responders in step 3, 2
(50%) showed response on adjuvants while remaining 2 (50%) did not respond.
This prompts us to look for a better adjuvant therapy in order to get the
absolute response at final stage of the protocol. Progression of disease stage
showed response to higher steps of pain relief in WHO step ladder protocol (‘p’
= 0.0001). 75.4 % patients amongst stage 2 were relieved at step 1 compared to
only 24 % of patients amongst stage 3. 30.7% patients in stage 3 needed step 2
and 44% needed step 3. majority of patients in stage 4 (80%) were relieved only
after step 3.
CoNClUSIoN
This
WHO guideline implementation study supports the use of algorithm for cancer
pain management. Effective pain relief was achieved in 95.3 % of our patients
with minimal side effects that could be easily managed. Pain management using
WHO algorithm must be an integral part of management of cancer cervix patients
throughtout the world.
ACKNoWlEDGEMENT
Sincere thanks to
Dr. Anita Mallik, Department of Anaesthesia, KGMU.
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