Acta Medica Scandinavica. Vol. CXIX, fasc. VI, 1944.

[From the medical clinic of the university of Aarhus, Denmark).

Uremia in morphine addicts. BY

CAI HOLTEN.

(Submitted for puhlication August 21, 1944).

I t is a well known fact that morphine addicts gradually become increasingly cachectic. In some cases suicide brings an end t o the patient's life, in other cases death is due to an intercurrent infec- lion. Some patients however die in a cachectic state without any manifest infection; in such cases the cause of death will presumably bc given as morphine cachexia.

However no satisfactory and sufficient explanation of the cachvxia has been given. In lliis paper 4 cases of chronic uremia in morphine addicts are reported. 2 of the patients, both of them cachectic, died froin uremia, and post niortem examinations showing severe renal damage have been undertaken. The other 2 patients were also more or less cachectic.

'The author feels that impairment of the kidney function may in some cases contribute in an important way to the development of the cachexia of morphine addicts. Even in severe uremia no alhurninuria may be found and the uremia is only disclosed by chemical examination of the blood. Hence these patients may very well die without the right diagnosis having been made.

Case htstories. Case Number 1. 1104/43, woman, 67 years old. Symptoms of gastric ulcer since 1932.

Congenital subluxation of right hip-joint, since 1932 much pain from de- forming arthrosis here. Several stays in hospitals for these diseases. Since

478 C A I H O L T E N .

1932 daily use of morphine in moderate doses. During s tay in hospital for 6 weeks, Oct-Nov. 1942 for depression, no albuminuria (6 examinations), readmitted in December 1942, transferred to mental hospital Jan. 1943. During this stay for some days frequent micturition, the urine con taiiied trace of albumin, bu t catheter specimen was normal and culture w t w negative. Morphint. was discontinued during the stays in hospitals, but after discharge the patient very soon resumed her use of this drug. On readmission July 23. 1943 she had hallucinations, was emaciated, pale and restless. On admission the urine contained no albumin. Catheter specimen was normal and culture was negative. Severe azotemia and acidosis was found (see below). Muscular twitchings were present. A tumor as large as a Jaffa orange could be felt over the symphysis (later proved to be a benign ovarial cyst).

She was given intravenous bicarbonate, fluids and diet arid improrcd considerably. She became quiet and the muscular twitchings gradually subsided. For 10 days falling doses of morphine were given till finally discontinued. She was discharged on Oct. 14th much improved and men- tally normal. On Now. 1st she was admitted to the surgical dept. and operated on for thc ovarial cyst. She died here on Nov. 14th 1943.

Laborato y findings etc. Urine 011 admission July 1943: 0 alb., later trace of alb. Catheter specimens: no casts, a few leucocytes, July 24th culture ncga-

Blood-urea: July 26th: 260, 27th: 250, Aug. 3.: 192, slowly decreasiirg,

Alkalireserve: July 26th: 22 vol. O h , 27th: 37 vol. %, July 31st: 69

Standard-clearance of urea: July 30th: 4 ml. per min. Addis' concentration test: July 31st: Maximum conc.: 1005. Total protein in Serum: 7.3-5.7 %. Urography: Aug. 14th: no excretion of perabrodil in pelves or hladdw.

Oftalmoscopy: no retinal changes. Blood pressure: 180/120, 200/110. Hemoglobin sicca: 60 yo, did not rise. Sedimentation rate: 93-100 mrn in 1 hour. Post mortem examlnation showed the heart moderately enlarged. The kidneys and urinary tract: no hydronephrosis. Kidneys contracted,

right 9 x 4 x 2 cm., left 9 x 4.5 x 2.5 cm. Capsule adherent, bu t strips easily. The surface is greyish-yellow with somewhat irregular granula- tion. The cortex is very narrow. On section the surface is greyish-yellow with disseminated minute cysts (2-3 mm).

tive, July 30th coli, Aug. 10th culture negative.

Oct. 15th: 134 mg yo.

vol. %.

The kidneys cannot be seen.

Height 161 cm. Weight: 47 kg.

Summary: Woman, 67 years old. Used opiates for about 11 years originally for pains from arthrosis of the hip-joint and gastric

I J R E M I A IN M O R P H I N E ADDICTS. 479

ulcer. During a stay in hospital in Dec. 1942 she had for a short time moderate dysuric syniptoms. The urine contained trace of albnmin, but catheter specimen was normal. July 1943 she was admitted with severe uremia. Renal function test showed severe impairment of function. Cali bacilli were found in the urine; albumi- nuria only present now and then. She died in November 1943 and post mortem examination showed contracted kidney probably of pyelonephritic type.

Case Number 11. 317/44, woman, 46 years old. Hemicrania since she was 19 years old.

Since 1932 she had used tablets with acetanilide. In 1934 in hospital for anemia toxica. The headache persisted; since 1937 she used pantopon daily, often scopolamine. In 1938 she was in hospital and the use of pan- topon (+ scopolamine) was stopped, but after discharge she very soon resumed her habit; during several stays in hospital she improved, but. these was no lasting effect. I n Dec. 1940 she had for the first time frequent and scanty micturitions, but the urine was normal. X-ray examination after perabrodil a t this time (Jan. 6th 1941) showed the kindeys of normal size, but the excretion was not good, however the pelves could just be discerned. On Jan. 5th 1943 she was admitted in a very serious condition, she was uremic (see below). The urine contained trace of albumin the next day. By treatment with fluids, bicarbonate and diet she improved, bu t was still emaciated and anemic on discharge March 12th 1943. On account of uremia she had to go to hospital several times till she at last died on Feb- ruary 14th 1944. She had used opiates at home and had steadily deterio- rated except for slight improvements during her stays in hospital. Albu- minuria was only found intermittently, and when present only slight tra- ces were found.

Laboratory findings etc.: Urine see above. Catheter-specimens never showed abnormal cells, 110 casts. Cultures negative. Blood urea: Jan. 6th 1943: 142, slowly decreasing, March 1943: 114,

Alkalireserve Jan. 7th 1943: 11, after a few days normal, Febr. 12. 1944:

Maximum-clearance: Febr. 12th, 1943: 13, June 2nd 1943: 11 ml. per

Addis concentration test: Febr. 28th 1943: Maximum conc. 1013. Total-protein: Jan. 7th 1943: 7.1 Yo. Urography (see also above): Febr. 17th 1943: no excretion. Ophtalmoscopy: no retinal changes. Blood pressure always normal.

Sept. 20th 1943: 98, Nov. 32th 1943: 88, Febr. 2nd 1944: 238 mg %.

a1 vol. yo.

n i inute.

480 CAI IIOLTEN.

Hemoglobin (sicca): 55 yo, normochromic anemia, some improvement

Weight: July 1938: 55 kg., Sept. 1943: 50 kg. X-ray examination of cranium: moderate frontal hyperostosis. Post mortem findings: Pyelonephritis chronica, Hydronephrosis duplex.

Hyperostosis frontalis. Anemia. Cholelithiasis. Both kidneys were small (right: 9 x 4 x 2.5 cm., left: 8 x 4.5 x 2.5

cm.) Capsule adherent. Surface very irregular with many small cysts and scars. On section several minute cysts, calyces dilated. Pelves and ureters dilated. Ureter measures 6 mm.

Microscopy: Pelvis thickened. Parenchyma very narrow. Considerable proliferation of the interstitial fibrous tissue, somewhat patchy, in the fibrous tissue considerable mononuclear infiltration. Glomeruli to a large extent fibrous or hyaline. In the fibrous tissue rests of small atrophic tubuli. Between the fibrous parts smaller parts with somewhat better parenchyma, here tubuli are dilated; here and there some glomeruli with less changes are seen. Arteries and artericles are very sclerotic.

by treatment, but rapid relapse.

Summary: woman, 46 years old, who on account of heniicrania had used first lablets with acetanilide, anemia had developed, later (since autumn 1938) she began to use opiates (pantopon and codeine). Slight and transient dysuric symptoms appeared in Dec. 1941. Kidney function was found impaired in Jan. 1942, uremia developed January 1943. Albuminuria was inconstant and slight. She died from uremia in Febr. 1944. $1 pyelonephritic con- tracted kidney was foiind.

Case humber 111. Woman, 43 years old. 26/44. Hemicrania since 1926, since 1932 tablets with 1 ctg. morphine and

1 ctg. codeine were taken 3-4 times a day. Tuberculous irritis from 1932, in hospital in 1934 and 1937, no albuminuria. 1941 her left eye was remov- vtl. June 1943 in neurosurgical dept., no albuminuria, transferred to medi- t al dept. July 29th 1943. She was pale, emaciated, very weak. For 2 or 3 !/ears moderate dysurie symptoms. Urine contained albumin, catheter speci- mens showed many leucocytes, culture: coli bacilli. Considerable azotemia, inoderate acidosis was found; severe anemia. Treatment with fluids, bicar- Ibonate and later sulphathiazol caused slow but steady improvement. Opia- ~ P S were gradually reduced, but she could not do without a little dilaudid (0.8 mg per day).

Laboratory findings etc.

' 1 ' 1 1 ~ albuminuria was a t the beginning about 0.5 O / i o o , presently 0. Urine: The pyuria was improved, but the urine did not become sterile.

Catheter spec.: see above.

U R E M I A I N M O R P H I N E ADDICTS. 48 1

Blood urea: July 30th: 170, Aug. 3rd: 240, Aug. 9th: 264, then rapidly

.Ilkali~eseroe: July 30: 40, Aug. 14: 58. V O ~ . %. M a x i m u m clearance: January 16th: 30 ml per minute, Febr. 12th; 17

Addis concentration test: January 22nd: 1010. Urography: Febr. 4th: delayed excretion, not till after 45 minutes vi-

Ophtalmoscopy: no retinal changes. Blood pressure: always normal. Hemoglobin (Yicea) duly 30th: 50 yo, normochromic anemia, Febr. 8th:

Il’ezght: Jail. 1935: 50 kg., July 1943: 38 kg., Febr. 1944: 40 kg.

decreasing, Aug. 19th: 118, Sept. 3rd: 80, Febr. 12th: 36 mg %.

nil per minute.

sib113 contrast in pelves. Kidneys seem to be rather small.

80 yo.

Summary: woman , 43 years old, with heinicrania and tuber- culous iritis, who for 12 years had used morphine and codeine in inoderate doses. For 2 years nioderate dysuric symptoms, on admission pyuria (Coli) and uremia good improveiiient on treat- nient, on discharge she had normal blood urea, but the kidney function was bad.

The sister of fhis putient had also hemicrania and had for niany years used morphine injections - during the last time 6 ctg. daily. She died in another hospital with a phlegmone fenmis and uremia (blood urea 220 Ing y’,).

Cast, Number 1V. Woman, 63 years old., 1503/43. Since 1928 trigeminus neuralgia, used large doses of ))mixed powders#

with acetanilide. Anemia found in 1928, resistent to treatment. 1935 operated on for neuralgia of the left Vth nerve without much effect.

Since 1936 she used gtt. thebaica comp. 30 drops 3 times a day = 6 ctg. opium per day; in bad periods she also had morphirle injections. Sweral febrile attacks of pyuria, firdt in 1938.

111 hospital Oct. 15th-Nov. 15th 1943 for weakuess and trigeminal neuralgia. She was pale, but not severely emaciated. The urine contained no albumin. Blood-urea was found elevated (see below).

She improved slightly on treatment with rest, F e and B vitamin.

Laboratory findings etc. Ur ine: see above. Catheter specimens: many leucocytes. Culture: bac. coli. Blood-urea: Oct. 26th: 68, 28th: 72, Nov. 9th: 78 nlg “/b. Maximum-clearance: 17 rnl per minute. .Addis concentration test: 1011.

482 CAI H O L T E N .

Urography: no excrrtioil, even after 8 hours. The right kidney mea- sures 10.5 x 5 cm., the left cannot he seen.

Total-protein in serum: 6.3 yo. Oftalmoscopy: no retinal changes. Blood-pressure: 155180, 160/90. Hemoglobin: (sicca): 65 yo, normochrome anemia, 110 certain improw-

Ewalds test meal: Achylia. Height: 163 cm. Weight: 55.7-54.7 kg.

Summary: 63 years old woman with trigeminal neuralgia Tor 15 years. For 7 years she had used opiates regularly. Several attacks of pyuria since 1938. In Oct. 1943 when no albuminuria was pre- sent her kidney function was found impaired (maximum-clearance 17 ml per minute, Addis test loll), blood-urea about 70 ing 04. pyuria (Coli) was present.

ment.

These patients have some clinical features in coninion. They are all women who for many years have used opiates for painful chronic diseases; the amount used is in all cases rather mode- rate. They have all had dysuric symptoms; these have occurred several years after the use of opiates had begun; the syinptoins have never been very pronounced, in 3 of the cases only consisting of frequent micturitions; only one of the patients had several years before azotemia was diagnosed had febrile attacks of pyuria. and she had, when azoteniia was found, no dysuric symptom whatever. Only slight and inconstant albuminuria was found, even if severe uremia was present. In 3 cases leucocytes and coli bacilli were found in catheter specimens of the urine, but the pyuria was not massive and cultures were not constantly positive. Post inor- tern examination in the fourth patient showed characteristic pyt.10- nephritic contracted kidney. So subjective symptoms from the uri- nary system were only slight and could easily be overlooked. As albuminuria was slight and transient, the headache, nausea, vo- miting, weakness and emaciation might easily have been ascribed to ,morphine cachexia)) combined with the other discases from which the patients were suffering., Functipn tests showed severe renal impairment in all cases. Retinal chhges were not found. Only 1 patient (67 years old) had definite elevation of the blood pressure. The doses of morphine used by these patients have as

L R E M I A I h M O R P H I N E A D D I C T S . 483

nirnlioned not been exceedingly large. One patient (case No 111) used about 4 ctg morphine + 4 ctg. codeine per day for about 11 pears; i t $ probable that her informations on this point were reli- able. Another patient (case No 11) used certainly more, hov, much cannot bg exactly stated; for the most time i t seems to have been 4 ctg. morphine + 8 -12 ctg. codeine phosphate daily; the use of opiates went on for about 6 years. One patient (No IV) used 6 ctg opium daily 4- injections of morphine in her bad periods. She used opiates for 7 years. In case No I the exact amount cannot be stated but seems to have been rather large, even if not exceedingly large, and the abuse went on for 12 years.

The pathological findings in the 2 patienls who died were very much alike. I t was the characteristic picture of the pyelonephritic contracted kidney. I t is reasonable to believe that the 2 other patients also have pyelonephritis Qith some degree of contraction.

Now one must ask whether the combination of chronic use of opiales and pyelonephritis with severe impairment of kidney function owing to chronic pyelonephritis is merely a coincidence or if a causal connection is present. Or to put the question in another manner: in which way may the prolonged use of opiates cause pyelonephritis? It is a well known fact that morphine may cause disturbance of micturition; the emptying of the bladder is difficult and incomplete partly because of the decreased desire to micturate, partly because of the effect of morphine on the autono- mic innervation of the bladder. This incomplete emptying of the bladder naturally disposes to infection of the urine, especially in women. Furthermore morphine has an effect on the ureter and renal pelvis which has been studied by Ockerblad (J. urology, 33, page 356, 1935). I t has been shown that morphine causes a rise of the ureteral pressure. This rise may conceivably cause some degree of stagnation of the urine in the pelvis, and this naturally again creates great possibilities for an infection to ascend into the renal parenchyma.

So i t seems quite reasonable to believe that the prolonged use of morphine may be the indirect cause of chronic pyelonephritis which ultimately may lead to pyelonephritic contracted kidney.

It is significant that all 4 patients were women who are much more liable to contract infection of the urinary tract than men.

I have not been able to find any cases of uremia in morphine

!

484 CAI H O L T E N .

addicts in the litterature. This is probably due to the fact previ- ously pointed out that urological symptoms are rather vague and the uremic symptoms are more or less obscured by the syinptonis of chronic niorphinismus. Furthermore patients with chronic morphi- nismus are mostly treated in mental hospitals where attention is generally not directed towards kidney function and the urinary tract.

A s the effect of morphine in these patients is not a toxic effect on the kidneys but a complication produced by the disposition to ascending infections caused by the effects of the drug on the urinary tract, i t is obvious that not all morphine addicts will show this complication. Men must be by far less exposed to it, and of course only a certain number of women will have their urinary tract infected. Ceteris paribus the longer the abuse has taken place the greater the proportion of patients with pyelonephritis. I have during recent years treated 8 morphine addicts in all, including the 4 patients referred to in this paper. The other 4 had no signs of pyelonephritis or renal damage.

They had been using opiates for

1)

3) 2years and

4 months, normal urine, noriiial kidney function 2) 10 )) )) P 0 R H

3 months )> n H H B

4) 8 years this latter patient had for the lasl 2 years not used opiates but dolantin which is somewhat like atropine in its effects on the autonomic nerves. Ockerblad has shown that atropine abolishes the effect of morphine on the ureteral pressure and no effect on the bladder is known. Hence 3 of these patients have been using opiates for a considerably shorter time than those described with renal damage. The fourth patient has never had dysuria, on examination in May 1944 she had normal urine and normal kidney function.

The material presented is small. But in view of the facts concerning the effects of opiates on the bladder and the irn- portants observations of Ockerblad, I believe that i t is sufficient to show a relationship between the prolonged use of opiates and renal damage owing to chronic pyelonephritis.

It would be interesting to have this suggestion confirmed by investigations on a large material of morphine addicts.

U R E M I A I N M O R P H I N E ADDICTS. 485

Summary.

4 cases of severe renal impairment owing l o chronic pyelonephri-' tis in women who had used opiates for a long time are reported. The dysuric symptoms have been very vague, signs of renal disease (albuminuria et c.) slight and transient so that the renal insuffi- ciency might easily have been overlooked.

The author suggests that chronic uremia may in some cases contribute to the cachexia in morphine addicts.