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A Clinical Determination of Pain Relief In Office Patients
A Clinical Determination of Pain Relief In Office Patients A Controlled Comparative Study A.
LEWIS KOLOD:"Y, ~1.D.
I:"TRODUcrlO:"
• The complex interaction of physiological, emotional and environmental factors in the production and awareness of pain leads the physician to constant evaluation of new analgesic agents and review of older ones. This allows for better selection of treatment that will effectively alleviate pain. Such evaluation presents many obstacles for the investigator. Qualitative measurements of pathological pain depends completely upon the acumen of the observer and the perceptiveness of the patient. As Lasagna' has noted, greatest reliance is still dependent upon the description of the subjective reaction. Evaluation of pain and its response to analgesic drugs can be effectively performed bv the clinician in his office practice. folio\\"i~g meticulous attention to the influencing variables encountered. Adequately controlled and well designed experiments may he very fruitful in yielding useful data. Potent narcotic analgesics are frequently used for relief of moderate to severe pain. Effective oral agents are of particular value because of convenience of administration. Since 1923, hydromorphone,~ a synthetic narcotic related to morphine, has been effectively used to control pain. ~10st clinicians have used this drug, parenterally. However, in recent years a numher of investigators have reported efficacy of the oral route."';' This study was carried out to determine the optimum dosage of hydromorphone when administered orally.
Allocation of identically appearing tablets that were packaged and numbered 1 to 102 was by randomization. As patients entered the study they were prescribed sequentially numbered packages. The experiment was double-blind, with neither patient nor physician being aware of the contents. Tablets were either placebo, hydromorphone o 2 mg. or hvdromorphone 4 mg. Administration was orally-one tablet four times per day. TAIlLE
I.
DEPICTS GROl'PS A:"D Group A (plac.·bo)
Dia~nosis
14 II 4
Trauma Rhf"llmatic
Plt'ural Headache
2
Group B (2 mg.)
---
(;roup C 14 mg.)
22 4 3 I
~4
7
2 I
2
Inf('ction HO(t~kin'!' ~t'\lritis
I>!.\(;:"OSIS
Ois('asc
(;all lIIadd.·r To.al
:14
2 34
34 ---_
..
_---
Group A consisted of 18 males and 16 females whose ages ranged from 15-66 years with a median of 43. Group B had seven males and 27 females with ages from 22-86, the median being 40; and Group Chad 19 females and 15 males with an age span of 16-73 years and a median of 41. CRITEHIA FOR
E\'ALUATIO~
OF RESULTS
This study included 102 office patients.
Clinical results were classified in terms of relief of pain: Complete - 100 per cent alleviation of pain \10derate - 50 per cent or more relief of pain, but not complete in 30-60 minutes.
Doctor Kolodnv is Head of Division of Rheumatology, North Charles General Hospital, Baltimore, Maryland.
o Hydromorphone is manufadured under the trademark, DILAUDID by the Knoll Pharmaceutical Company, Orange, New Jersey.
METHOD AND PROCEDURE
Janllary-Ft·bmary, 1966
11
PSYCHOSO\IATICS T,\BLE III.
Mild - 50 per cent or less relief of pain. but more than no relief l'\one - no relief after 1 hour. Most patients can differentiate these differences. Side effects and mood were also carefully noted. T.\BI.E II.
------St'\'rrc
A
modt'ratt' mild ---
Dt'~H'C
De-grec of Pain
Group
----- ---!o.eVeTe
B
modt'ratc mild
--
-
romplt,tt, modt'rate
:18." tiLl!
lIIodt>rah'
:\\'('ra~('
Duration of
R,·lid
'k
(hr~ ;
17.fi :!~I..I
nUlu'
H.7 :IlU
rOIllI)I.,lt"
:!ll.li
IlH.dt'rat,'
mild
H.\ 2tl.:1
nOtH'
lUI
mild
:!.:!!)
------
:,5.9 44.1
complclt·
-11."
5l!.8
I1lOdcratl'
mild
mild
:1.',4
t;-t.7 H.7 H.7
4.1:\
;-.. 11
nOllt"
Grnup .\ plact"ho)
I :\Ollt"
:'Jaust'a VOmilinl( Epigastric. distn'ss Dilliness Dro\\'situ"!\s Dryness mouth Pruriws
Gnlup 8
Group C
mI;. ,
(4 m~.)
(2
:!7 1
:!.~
'I
2
:1
17 7
""
2
II
\ I
:~
8
"
II
2 II
4
<' I
"
of
R,·lid
'Ie
----_._--St'\'crc
C
RESL'LTS
SIDE EFFECTS
From the ahove tahle it can be seen that Group A (placeho) showed moderate to complete relief of pain in 4i.0 per cent of the cases. Anxietv was ameliorated in five out of the 18 patients that showed it prior to treatment. Seven patients got worse and two developed anxiety after medication. With Group B (hydromorphone 2 mg.) there was complet(· to moderate relief in 6·17
per cent of the cases. Of these patients 2-1 had detectable anxietv before treatment and one patient was depr~ssed. After medication the depressed person remained unchanged and seven with anxiety improved; four became worse and 13 remained the same. Of Group C (hydromorphone 4 mg.) i9.-l per cent had complete to moderate relief. Twenty-one patients were suffering from anxiety and of these, seven received relief of the symptom; one became worse and 12 were unchanged. Euphoria was ohserved in one patient and anxiety developed in two who were considered to have a state of well-being prior to medication. Figure I illustrates the response to therapy employed. As may he seen from Table III, side-effects were more frequently observed with the larger doses. DISCUSSIO:"
10'0
0 • no rei ief
95 90
I
- mi Id .-el ief
2 • moderate roe 1 i 6 f 3 - cornp I ete re lie f
85 90
75
-
70
65
60 ~
55 ~ 50 ~ 45
ll.
~ 40 ~
35
-
~ 30 Q:
~
25 20 15
'0
- -
5
o
o
Fig. 1.
12
I 2 3 GROUP A PLACEBO
-
-
r o
-
1""-
r I
2
3 GROuP B
o
I
2
3
HYORCMORPHONE
GROuP C HYORCMORPHONE
2 mg.
4 mg.
Degree of pain relief.
In studying the effect of a drug on the pain symptom, the investigator is faced with many variahles and extraneous conditions which may influence his data.' Elimination of ohserver hias, evaluation of psychic factors and determination of proper dosage are necessary to obtain valid and useful results. Even the personality of the investigator may exert an influence upon an experiment of this type. In designing a double-hlind study it is both necessary and important to anticipate differences hetween the test drugs so that adequate data may be recorded. Similarity in studied groups insofar as age, sex and disease may contrihute to the validity of the experiment. Randomization lessens the chance of error. In this study, the aforementioned variables were considered. Statistical analysis, comparing the three Groups showed a chi square equal to 72.35 with significance greater than 0.001. Considerable analgesic effect was ohserved in the placebo group, hut in no way Volume VII
PAIN RELIEF IN OFFICE PATIENTS-KOLODNY
did these effects approach the analgesic response after oral administration of either the 2 or the 4 mg. tablets of hydromorphone. However, administration of 4 mg. of hydromorphone with its increased analgesic action and increased duration of action. far offsets the increased incidence of side-effects. Sl':<.L\[ARY AND CONCLUSIONS
Analgesic potency of hydromorphone was studied in 102 office patients suffering with pain from a wide variety of causes. In a douhle-hlind designed experiment 2 mg. and 4 mg. of hydromorphone (Dilaudid) were compared with a placeho. Drugs were administered orally. Complete to moderate pain relief was ohtained in 79.4 per cent of the patients receiving 4 mg. of hydromorphone: 64.7 per cent of those receiving 2 mg. of the drug reported similar relief. Only 47.0 per cent of the group receiving a placeho experienced complete to moderate relief. These differences are highly significant hy chi square analysis. It should he noted that the 4 mg. oral dose of hydromorphone produced complete relief of pain in 64.7 per cent of the patients in comparison with 17.6 per cent of those receiving placehos. Side effects were more fre-
quently observed at the 4 mg. dose level but these were outweighed by the advantages of the significant increase in the degree and duration of analgesia produced. This study indicates that the oral dosage of hydromorphone should he governed by the degree of pain being treated; moderate pain can be controlled with as little as 2 mg. orally while more severe pain will require a 4 mg. dose. BIBLIOGRAPHY
1. Lasagna, L.: The Clinical Measurement of Pain. Ann. Neu: York Acad. Sc. 86:28, 1980. 2. Knoll & Co.: DRP 365, 683. jahresher chem Tech 49:2, 1923; DRP 380, 191. ibid. 49: 122, 1923. 3. Becker, ~I.: An Oral Narcotic Analgesic in Private Practice. Med. Times 89:1317, 1961. 4. \Ienard, O. J.: Dilaudid for Intractable Pain. Sur/!. Clin. N. Amer. 13:727, 1933. 5. ~Ialoney, A. H.: Some Snbjective Symptoms in Dilaudid \1edication, ]. Nat. "lee!. Ass. 29:49, 1937. 6. Cass, L. J. and Frederik, W. S.: A Controlled Clinical Evaluation of the Analgesic Effect of Oral Hydromorphone. Curro Therap. He's. 7 :275. 1965. ,. Coldhcrg, R. I. and Shuman, F. I.: Oral Hydromorphonc in Trauma. Curro T1ICTClp. Hes. 7: 284. 1965. 8. Beecher, H. K. d al: Field Use of \Idhadone and Le\'oisomethadone in a Combat ZOIll' (Ham11IIng-Hnngnam, l':orth Korea), U. S. A.rllled Pom's \1. J. 2: 1269, 1951. 182.5 Eastern Boulevard Raltilllore, Mar!llOll
It has long Iwen my hopt' that psychiatrists in my time would discard tilt' theoretical vagaries and pretentious isolations of the Freudian era, once again reeognize the indivisibility of psychiatry and general medicine, and reassumt' tllt'ir ohligations in compreh('nsive and progressive medical edut'ation.-Juu:s ~1ASSEHMAN, M.D., Current Psyc1liatric Therapies: Nt"" York: Cmne & Stratton. 1965.
January-F.·bmary, 1966
LEWIS KOLOD:"Y, ~1.D.
I:"TRODUcrlO:"
• The complex interaction of physiological, emotional and environmental factors in the production and awareness of pain leads the physician to constant evaluation of new analgesic agents and review of older ones. This allows for better selection of treatment that will effectively alleviate pain. Such evaluation presents many obstacles for the investigator. Qualitative measurements of pathological pain depends completely upon the acumen of the observer and the perceptiveness of the patient. As Lasagna' has noted, greatest reliance is still dependent upon the description of the subjective reaction. Evaluation of pain and its response to analgesic drugs can be effectively performed bv the clinician in his office practice. folio\\"i~g meticulous attention to the influencing variables encountered. Adequately controlled and well designed experiments may he very fruitful in yielding useful data. Potent narcotic analgesics are frequently used for relief of moderate to severe pain. Effective oral agents are of particular value because of convenience of administration. Since 1923, hydromorphone,~ a synthetic narcotic related to morphine, has been effectively used to control pain. ~10st clinicians have used this drug, parenterally. However, in recent years a numher of investigators have reported efficacy of the oral route."';' This study was carried out to determine the optimum dosage of hydromorphone when administered orally.
Allocation of identically appearing tablets that were packaged and numbered 1 to 102 was by randomization. As patients entered the study they were prescribed sequentially numbered packages. The experiment was double-blind, with neither patient nor physician being aware of the contents. Tablets were either placebo, hydromorphone o 2 mg. or hvdromorphone 4 mg. Administration was orally-one tablet four times per day. TAIlLE
I.
DEPICTS GROl'PS A:"D Group A (plac.·bo)
Dia~nosis
14 II 4
Trauma Rhf"llmatic
Plt'ural Headache
2
Group B (2 mg.)
---
(;roup C 14 mg.)
22 4 3 I
~4
7
2 I
2
Inf('ction HO(t~kin'!' ~t'\lritis
I>!.\(;:"OSIS
Ois('asc
(;all lIIadd.·r To.al
:14
2 34
34 ---_
..
_---
Group A consisted of 18 males and 16 females whose ages ranged from 15-66 years with a median of 43. Group B had seven males and 27 females with ages from 22-86, the median being 40; and Group Chad 19 females and 15 males with an age span of 16-73 years and a median of 41. CRITEHIA FOR
E\'ALUATIO~
OF RESULTS
This study included 102 office patients.
Clinical results were classified in terms of relief of pain: Complete - 100 per cent alleviation of pain \10derate - 50 per cent or more relief of pain, but not complete in 30-60 minutes.
Doctor Kolodnv is Head of Division of Rheumatology, North Charles General Hospital, Baltimore, Maryland.
o Hydromorphone is manufadured under the trademark, DILAUDID by the Knoll Pharmaceutical Company, Orange, New Jersey.
METHOD AND PROCEDURE
Janllary-Ft·bmary, 1966
11
PSYCHOSO\IATICS T,\BLE III.
Mild - 50 per cent or less relief of pain. but more than no relief l'\one - no relief after 1 hour. Most patients can differentiate these differences. Side effects and mood were also carefully noted. T.\BI.E II.
------St'\'rrc
A
modt'ratt' mild ---
Dt'~H'C
De-grec of Pain
Group
----- ---!o.eVeTe
B
modt'ratc mild
--
-
romplt,tt, modt'rate
:18." tiLl!
lIIodt>rah'
:\\'('ra~('
Duration of
R,·lid
'k
(hr~ ;
17.fi :!~I..I
nUlu'
H.7 :IlU
rOIllI)I.,lt"
:!ll.li
IlH.dt'rat,'
mild
H.\ 2tl.:1
nOtH'
lUI
mild
:!.:!!)
------
:,5.9 44.1
complclt·
-11."
5l!.8
I1lOdcratl'
mild
mild
:1.',4
t;-t.7 H.7 H.7
4.1:\
;-.. 11
nOllt"
Grnup .\ plact"ho)
I :\Ollt"
:'Jaust'a VOmilinl( Epigastric. distn'ss Dilliness Dro\\'situ"!\s Dryness mouth Pruriws
Gnlup 8
Group C
mI;. ,
(4 m~.)
(2
:!7 1
:!.~
'I
2
:1
17 7
""
2
II
\ I
:~
8
"
II
2 II
4
<' I
"
of
R,·lid
'Ie
----_._--St'\'crc
C
RESL'LTS
SIDE EFFECTS
From the ahove tahle it can be seen that Group A (placeho) showed moderate to complete relief of pain in 4i.0 per cent of the cases. Anxietv was ameliorated in five out of the 18 patients that showed it prior to treatment. Seven patients got worse and two developed anxiety after medication. With Group B (hydromorphone 2 mg.) there was complet(· to moderate relief in 6·17
per cent of the cases. Of these patients 2-1 had detectable anxietv before treatment and one patient was depr~ssed. After medication the depressed person remained unchanged and seven with anxiety improved; four became worse and 13 remained the same. Of Group C (hydromorphone 4 mg.) i9.-l per cent had complete to moderate relief. Twenty-one patients were suffering from anxiety and of these, seven received relief of the symptom; one became worse and 12 were unchanged. Euphoria was ohserved in one patient and anxiety developed in two who were considered to have a state of well-being prior to medication. Figure I illustrates the response to therapy employed. As may he seen from Table III, side-effects were more frequently observed with the larger doses. DISCUSSIO:"
10'0
0 • no rei ief
95 90
I
- mi Id .-el ief
2 • moderate roe 1 i 6 f 3 - cornp I ete re lie f
85 90
75
-
70
65
60 ~
55 ~ 50 ~ 45
ll.
~ 40 ~
35
-
~ 30 Q:
~
25 20 15
'0
- -
5
o
o
Fig. 1.
12
I 2 3 GROUP A PLACEBO
-
-
r o
-
1""-
r I
2
3 GROuP B
o
I
2
3
HYORCMORPHONE
GROuP C HYORCMORPHONE
2 mg.
4 mg.
Degree of pain relief.
In studying the effect of a drug on the pain symptom, the investigator is faced with many variahles and extraneous conditions which may influence his data.' Elimination of ohserver hias, evaluation of psychic factors and determination of proper dosage are necessary to obtain valid and useful results. Even the personality of the investigator may exert an influence upon an experiment of this type. In designing a double-hlind study it is both necessary and important to anticipate differences hetween the test drugs so that adequate data may be recorded. Similarity in studied groups insofar as age, sex and disease may contrihute to the validity of the experiment. Randomization lessens the chance of error. In this study, the aforementioned variables were considered. Statistical analysis, comparing the three Groups showed a chi square equal to 72.35 with significance greater than 0.001. Considerable analgesic effect was ohserved in the placebo group, hut in no way Volume VII
PAIN RELIEF IN OFFICE PATIENTS-KOLODNY
did these effects approach the analgesic response after oral administration of either the 2 or the 4 mg. tablets of hydromorphone. However, administration of 4 mg. of hydromorphone with its increased analgesic action and increased duration of action. far offsets the increased incidence of side-effects. Sl':<.L\[ARY AND CONCLUSIONS
Analgesic potency of hydromorphone was studied in 102 office patients suffering with pain from a wide variety of causes. In a douhle-hlind designed experiment 2 mg. and 4 mg. of hydromorphone (Dilaudid) were compared with a placeho. Drugs were administered orally. Complete to moderate pain relief was ohtained in 79.4 per cent of the patients receiving 4 mg. of hydromorphone: 64.7 per cent of those receiving 2 mg. of the drug reported similar relief. Only 47.0 per cent of the group receiving a placeho experienced complete to moderate relief. These differences are highly significant hy chi square analysis. It should he noted that the 4 mg. oral dose of hydromorphone produced complete relief of pain in 64.7 per cent of the patients in comparison with 17.6 per cent of those receiving placehos. Side effects were more fre-
quently observed at the 4 mg. dose level but these were outweighed by the advantages of the significant increase in the degree and duration of analgesia produced. This study indicates that the oral dosage of hydromorphone should he governed by the degree of pain being treated; moderate pain can be controlled with as little as 2 mg. orally while more severe pain will require a 4 mg. dose. BIBLIOGRAPHY
1. Lasagna, L.: The Clinical Measurement of Pain. Ann. Neu: York Acad. Sc. 86:28, 1980. 2. Knoll & Co.: DRP 365, 683. jahresher chem Tech 49:2, 1923; DRP 380, 191. ibid. 49: 122, 1923. 3. Becker, ~I.: An Oral Narcotic Analgesic in Private Practice. Med. Times 89:1317, 1961. 4. \Ienard, O. J.: Dilaudid for Intractable Pain. Sur/!. Clin. N. Amer. 13:727, 1933. 5. ~Ialoney, A. H.: Some Snbjective Symptoms in Dilaudid \1edication, ]. Nat. "lee!. Ass. 29:49, 1937. 6. Cass, L. J. and Frederik, W. S.: A Controlled Clinical Evaluation of the Analgesic Effect of Oral Hydromorphone. Curro Therap. He's. 7 :275. 1965. ,. Coldhcrg, R. I. and Shuman, F. I.: Oral Hydromorphonc in Trauma. Curro T1ICTClp. Hes. 7: 284. 1965. 8. Beecher, H. K. d al: Field Use of \Idhadone and Le\'oisomethadone in a Combat ZOIll' (Ham11IIng-Hnngnam, l':orth Korea), U. S. A.rllled Pom's \1. J. 2: 1269, 1951. 182.5 Eastern Boulevard Raltilllore, Mar!llOll
It has long Iwen my hopt' that psychiatrists in my time would discard tilt' theoretical vagaries and pretentious isolations of the Freudian era, once again reeognize the indivisibility of psychiatry and general medicine, and reassumt' tllt'ir ohligations in compreh('nsive and progressive medical edut'ation.-Juu:s ~1ASSEHMAN, M.D., Current Psyc1liatric Therapies: Nt"" York: Cmne & Stratton. 1965.
January-F.·bmary, 1966