The rise and fall of the dolorimeter: Pain, analgesics, and the management of subjectivity in mid-twentieth-century United States

Journal of the History of Medicine and Allied Sciences

Volumn 66, Issue 2, 2011, Pages 145-179

  Tousignant, Noémi ^a  

^a LONDON SCHOOL OF HYGIENE AND TROPICAL MEDICINE   (United Kingdom)

Author keywords

analgesic; clinical trials; objectivity; pain; quantification; subjectivity

Indexed keywords

ANALGESIC AGENT;

ANALGESIA; ARTICLE; CLINICAL TRIAL (TOPIC); HISTORY; HUMAN; MEDICAL RESEARCH; METHODOLOGY; NOCICEPTION; PAIN; PAIN ASSESSMENT; UNITED STATES;

ANALGESIA; ANALGESICS; BIOMEDICAL RESEARCH; CLINICAL TRIALS AS TOPIC; HISTORY, 20TH CENTURY; HUMANS; PAIN; PAIN MEASUREMENT; PAIN PERCEPTION; UNITED STATES;

EID: 79954449480     PISSN: 00225045     EISSN: 14684373     Source Type: Journal    
DOI: 10.1093/jhmas/jrq024     Document Type: Article

References (132)

1. James D. Hardy, Harold G. Wolff, and Helen Goodell, "Studies on Pain. A New Method for Measuring Pain Threshold: Observations on the Spatial Summation of Pain," J. Clin. Invest., 1940, 19, 649-57.
2. Edwin G. Boring, Sensation and Perception in the History of Psychology (New York: Appleton-Century Company, 1942); Roselyne Rey, The History of Pain, trans. Louise Elliott Wallace (Cambridge, Massachusetts: Harvard University Press, 1995).
3. Alfred C. Haddon, ed., Reports of the Cambridge Anthropological Expedition to Torres Straits, 6 vols. (Cambridge: University Press, 1901-35), II: 194; Gina Lombroso-Ferrero, Criminal Man (Montclair, New Jersey: Patterson Smith, 1972), 246-49; Cesare Lombroso, Nouvelles Recherches de Psychiatrie et d'Anthropologie Criminelle (Paris:
4. F. Alcan, 1892), 88; Mary Gibson, "On the Insensitivity of Women: Science and the Woman Question in Liberal Italy, 1890-1910," J. Women's Hist., 1990, 2, 11-41.
5. Anon., "Brothers under the Skin: We All Feel Pain in Same Way, National Academy Is Told," Newsweek (6 May 1940) in Harold G. Wolff Papers (1922-70), Box 1, Folder 6, Medical Center Archives of New York-Presbyterian/ Weill Cornell, New York (hereafter, Wolff Papers).
6. Hardy, Wolff, and Goodell, "Studies on Pain"; James D. Hardy et al., Pain Sensations and Reactions (Baltimore: Williams & Wilkins, 1952).
7. G. Woolfe and A. D. Macdonald, "The Evaluation of the Analgesic Action of Pethidine Hydrochloride (Demerol)," J. Pharmacol. Exp. Ther., 1944, 80, 300-7.
8. Lyndon E. Lee, "Medication in the Control of Pain in Terminal Cancer, with Reference to the Study of Newer Synthetic Analgesics," J. Am. Med. Assoc., 1941, 116, 216-20.
9. D. I. Macht, N. B. Herman, and C. S. Levy, "A Quantitative Study of the Analgesia Produced by Opium Alkaloids, Individually and in Combination with Each Other, in Normal Man," J. Pharmacol. Exp. Ther., 1916, 8, 1-37.
10. Richard B. Malmo et al., "Standardized Pain Stimulation as Controlled Stress in Physiological Studies of Psychoneurosis," Science, 1948, 108, 509-11
11. William P. Chapman et al., "Measurements of Pain Sensitivity in Patients with Psychoneurosis," Arch. Neurol. Psychiatry, 1947, 57, 321-31.
12. This approximate number was calculated from my literature review and the bibliography provided by A. H. Kutscher and H. W. Kutscher, "Evaluation of the Hardy-Wolff- Goodell Pain Threshold Apparatus and Technique: Review of the Literature," Int. Rec. Med. Gen. Pract. Clin., 1957, 170, 202-12, passim.
13. Harold G. Wolff and Henry S. Dunning, "The Teaching of Clinical Neurology," J. Assoc. Am. Med. Coll., 1947, 22, 263-73
14. R. A. Kuhn and R. B. Bromiley, "Human Pain Thresholds Determined by the Radiant Heat Technique and the Effect upon Them of Acetylsalicylic Acid, Morphine Sulfate, and Sodium Phenobarbitol," J. Pharmacol. Exp. Ther., 1951, 101, 47-55.
15. L. C. Miller, "A Critique of Analgesic Testing Methods," Ann. N. Y. Acad. Sci., 1948, 51, 34-50, provides this information. The Co-Design Corporation would also market the dolorimeter a few years later: sales pamphlet for the Hardy-Wolff-Goodell Dolorimeter, Co-Design Corporation, Winchester, Massachusetts, n.d.; Box 3, Folder 12, Wolff Papers.
16. Miller, "A Critique."
17. Donald E. Williamson to Janet Travell, 16 June 1953, Box 19, Folder 30, Janet Travell Papers, George Washington University Archives, Washington, DC.
18. This trend is suggested in the number of publications reporting results using the dolorimeter in my own literature review and confirmed by the references enumerated in the bibliography provided by Kutscher and Kutscher, "Evaluation," 228-30. It is of course possible that the dolorimeter was still in use after 1950, but that results were rarely published. For example, in 1953, one group reported that they still used the dolorimeter, but only as a test preliminary to clinical studies. See S. C. Cullen and E. G. Gross, "Analgesic Testing Methods," Bulletin of the Committee on Drug Addiction and Narcotics, 1953, 626. Nevertheless, it seems unlikely that the method was widely used.
19. Henry K. Beecher, "Experimental Pharmacology and the Measurement of Subjective Response," Science, 1952, 116, 157-62
20. James D. Hardy, Harold G. Wolff, and Helen Goodell, "Pain-Controlled and Uncontrolled," Science, 1953, 117, 164-67
21. Beecher, "Pain-Controlled and Uncontrolled. Rejoinder to Dr. Hardy, Dr. Wolff and Miss Goodell," Science, 1953, 117, 164-67.
22. Harry M. Marks, The Progress of Experiment: Science and Therapeutic Reform in the United States, 1900-1990 (Cambridge: Cambridge University Press, 1997).
23. Isabelle Baszanger, Inventing Pain Medicine from the Laboratory to the Clinic (New Brunswick, New Jersey: Rutgers University Press, 1998).
24. Marcia L. Meldrum, "'Departures from the Design': The Randomized Clinical Trial in Historical Context, 1946-1970" (PhD diss., Department of History, State University of New York at Stony Brook, 1994), on how the clinical trial was adapted by Beecher for the evaluation of analgesic drugs.
25. H. G. Wolff, J. Hardy, and H. Goodell "Studies on Pain. Measurement of the Effect of Morphine, Codeine and Other Opiates on the Pain Threshold and an Analysis of Their Relation to the Pain Experience," J. Clin. Invest., 1940, 19, 659-80.
26. Beecher, "Experimental Pharmacology," 160.
27. Jane E. Denton and Henry K. Beecher, "New Analgesics. I. Methods in the Clinical Evaluation of New Analgesics," J. Am. Med. Assoc., 1949, 141, 1051-57.
28. Harold G. Wolff, "Cornell Conference on Therapy: Psychologic Aspects of Treatment of Pain," N. Y. State Med. J., 1945, 45, 1003-9.
29. Hardy, Wolff, and Goodell, "Pain-Controlled and Uncontrolled," 165.
30. Although Hardy, Wolff, and Goodell initially claimed that their instrument worked with untrained subjects, they later admitted the importance of practice and instruction (they used the term familiarization rather than training) to obtain more consistent pain thresholds, see: Hardy, Pain Sensations. The following authors used subjects who had been trained or were familiar with the dolorimeter: H. L. Andrews, "Skin Resistance Changes and Measurements of Pain Threshold," J. Clin. Invest., 1943, 22, 517-20
31. E. G. Gross, H. L. Holland, and F. W. Schueler, "Human Studies of Piperidine Derivatives," J. Appl. Physiol., 1948, 1, 298-303
32. C. C. Scott, K. G. Kohlstaedt, and K. K. Chen, "Comparison of the Pharmacologic Properties of Some New Analgesic Substances," Anesth. Analg., 1947, 26, 12-17
33. F. B. Flinn and A. S. Chaikelis, "An Improved Instrument for the Determination of Changes in the Pain Threshold Caused by Drugs," Am. J. Psychiatry, 1946-47, 103, 349-50.
34. Arthur S. Keats, Henry K. Beecher, and Frederick C. Mosteller, "Measurement of Pathological Pain in Distinction to Experimental Pain," J. Exp. Physiol., 1950, 3, 35
35. Beecher had formulated this idea earlier, but it was only in the later article that he discussed its implications for analgesic testing. See "Pain in Men Wounded in Battle," Bull. U. S. Army Med. Dep., 1946, 5, 445-54.
36. Beecher, "Experimental Pharmacology."
37. Louis Lasagna, Frederic Mosteller, John M. von Felsinger, and Henry K. Beecher, "A Study of the Placebo Response," Am. J. Med., 1954, 16, 770-79, determining a technique to screen out placebo responders from analgesic clinical trials was cited as one of the rationales for this study. However, later results showed that it was very difficult, if not impossible, to identify those who would respond to placebos consistently.
38. Marcia Meldrum, "Each Patient His Own Control: James Hardy and Henry Beecher on the Problem of Pain Measurement," Am. Pain Soc. Bull., 1999, 1, http://www.ampainsoc.org/pub/bulletin/jan99/history.htm (accessed 29 September 2003).
39. Henry K. Beecher, "A Method for Quantifying the Intensity of Pain," Science, 1953, 118, 322-24.
40. Beecher, "Experimental Pharmacology," 160.
41. Sales pamphlet, Wolff Papers; "Report to the Surgeon General on his visit to Wolff 's laboratory by H. L. Andrews, July 28, 1939," Projects: Development of Nonaddictive Analgesics: Clinical Studies: PHS Hospital: Lexington General, CDA, National Academies of Sciences Archives, Washington, DC (hereafter CDA-NASA).
42. Beecher, "Pain-Controlled and Uncontrolled," 167.
43. Oral History Interview with Louis Lasagna, 8 September 1995 (Ms. Coll. no. 127.19), 6, John C. Liebeskind History of Pain Collection, History & Special Collections Division, Louise M. Darling Biomedical Library, University of California, Los Angeles.
44. "Obituary," Box 1, Folder 1, Wolff Papers.
45. H. G. Wolff and Martin Tunis, "Studies on Headache: Further Observations on Cranial and Conjunctival Vessels during and between Vascular Headache Attacks," manuscript in lecture, misc., 1950s, Box 12, Wolff Papers.
46. "Migraine Sensitivity Threshold Experiments," 1936-1940, Box 12, Wolff papers. See also Harold G. Wolff, Dean Clark, and Heloise Hough, "Experimental Studies on Headache: Observations on Headache Produced by Histamine," Arch. Neurol. Psychiatry 1936, 35, 1054-69.
47. Wolff, Hardy, and Goodell, "Studies on Pain. Measurement of the Effect."
48. W. C. White to Walter Treadway, 8 May 1939, Projects: Development of Nonaddictive Analgesics: Clinical Studies: PHS Hospital: Lexington General, CDA-NASA.
49. Caroline J. Acker, Creating the American Junkie: Addiction Research in the Classic Era of Narcotic Control (Baltimore: Johns Hopkins University Press, 2002), 65. Until 1940, funding for the Committee was provided in large part by the Rockefeller Foundation.
50. Nathan B. Eddy, The National Research Council Involvement in the Opiate Problem, 1928-1971 (Washington, DC: National Academies of Science, 1973), 19. In the first two-and-a-half years of the program, sixty-six substances were sent by the chemistry laboratory, based at the University of Virginia for pharmacological testing at the University of Michigan.
51. Nathan B. Eddy, "Studies on Morphine, Codeine and Their Derivatives," J. Pharm. Exp. Ther., 1932, 45, 339-59.
52. Walter Treadway (Office of the Surgeon General) to W. Charles White, 30 April 1935, Projects: Development of Nonaddictive Analgesics: Clinical studies: PHS Hospital: Lexington General, CDA-NASA.
53. H. S. Cumming (Surgeon General) to Henry D. Chadwick (Commissioner of Public Health), 23 June 1934, Projects: Development of Nonaddictive Analgesics: Clinical Studies: Pondville Hospital, CDA-NASA.
54. N. B. Eddy to W. C. White, 24 April 1935, Projects: Development of Nonaddictive Analgesics: Clinical Studies: Pondville Hospital, CDA-NASA. In this letter, Eddy points out that the drug might still be valuable because of its intensity, but that, in order to determine this, information about the minimal effective clinical dose was needed, on the basis of which it would be possible to conduct a trial "under the most rigid and close control of our organization."
55. N. B. Eddy to C. K. Himmelsbach, 15 July 1935, Projects: Development of Nonaddictive Analgesics: Clinical Studies: PHS Hospital: Lexington General, CDA-NASA;
56. A. S. Pope to W. C. White, 23 March 1937, Projects: Development of Nonaddictive Analgesics: Clinical Studies: Pondville Hospital, CDA-NASA; Eddy to White, 24 April 1935.
57. Otniel E. Dror, "The Scientific Image of Emotion: Experience and Technologies of Inscription," Configurations, 1999, 7, 366-67.
58. The Director of Laboratories at Lexington Hospital reported to the Committee that "judgemental and interpretive factors were of more significance in producing pain than any particular degree of stimulation" and to abandon intensive work along these lines: E. Williams, "A Quantitative Measure of Analgesia (Summary of Work Done at Lexington in Past Year, November 12, 1938
59. L. Kolb to W. C. White, 12 November 1938, Projects: Development of Nonaddictive Analgesics: Clinical Studies: PHS Hospital: Lexington General, CDA-NASA.
60. The studies were carried out at the University of Michigan Hospital, Pondville Cancer Hospital, Walter Reed Army Hospital, Marine Hospital, and eventually theMassachusetts General Hospital. Access to these sites was enabled by the Committee's alliances.
61. "Memorandum Number 2, June 18, 1936," Projects: Development of Nonaddictive Analgesics: Clinical Studies: Pondville Hospital: CDA-NASA; N. B. Eddy to General R. F. Metcalfe, 18 November 1938, Projects: Development of Nonaddictive Analgesics: Clinical Studies: Walter Reed General Hospital, CDA-NASA.
62. "Report on Work on Analgesia at the University of Michigan, October 6, 1937," Projects: Development of Nonaddictive Analgesics: Clinical Studies: University of Michigan Hospital, CDA-NASA; "Memorandum Number 2, June 18, 1936."
63. L. E. Lee to W. C. White, 8 December 1938, Projects: Development of Nonaddictive Analgesics: Clinical Studies: Pondville Hospital, CDA-NASA: "Admissions to Pondville Hospital are at a low ebb at present, consequently suitable study cases appear very infrequently
64. said O. E. Denney to N. B. Eddy, 13 November 1939, Projects: Development of Nonaddictive Analgesics: Clinical Studies: Marine Hospital, 1938-1939, CDA-NASA. Descriptions of individual patients and the problems in using them for analgesic studies can be found in the Committee's correspondence. For example, in this letter, Denney describes one patient as being: "a highly emotional, unstable person."
65. Anon., "Observations on the metopon study," October 1947, Projects: Development of Nonaddictive Analgesics: Metopon, CDA-NASA.
66. W. C. White to Harold G. Wolff, c.c. L. E. Lee, H. L. Andrews, and L. Kolb, 30 June 1939, Projects: Development of Nonaddictive Analgesics: Clinical Studies: PHS Hospital: Lexington General, CDA-NASA.
67. H. L. Andrews to W. C. White, 28 July 1939, Projects: Development of Nonaddictive Analgesics: Clinical Studies: PHS Hospital: Lexington General, CDA-NASA. "Report to the Surgeon General on his visit to Wolff 's laboratory by H. L. Andrews, 28 July 1939," Projects: Development of Nonaddictive Analgesics: Clinical Studies: PHS Hospital: Lexington General, CDA-NASA.
68. L. E. Lee to W. C. White, 24 July 1939, Projects: Development of Nonaddictive Analgesics: Clinical Studies: PHS Hospital: Lexington General, CDA-NASA, noted "the uniformity of Dr. Wolff 's results with a small group of subjects is remarkable
69. Report to the Surgeon General on his visit to Wolff 's laboratory by H. L. Andrews, July 28,1939," likewise commented "The fact that the threshold has practically the same value for all normal individuals is another feature in favor of the method
70. N. B. Eddy to Howard L. Andrews, 30 June 1939, Projects: Development of Nonaddictive Analgesics: Clinical Studies: PHS Hospital: Lexington General, CDA-NASA; H. L. Andrews "Report to theSurgeon General," c. 1939-40, Projects: Development of Nonaddictive Analgesics: Clinical Studies: PHS Hospital: Lexington General, CDA-NASA.
71. L. E. Lee to W. C. White, 24 July 1939.
72. Demerol was also called meperidine in the United States, and known in various countries as dolantin (the name it was first given by the German researchers), isonipecaine, dolantol, dolasol, pethidine (often used by British researchers), mefedine, and lidol; this drug was first synthesized by Eisleb and Schaumann in Germany and approved in the United States by the Food and Drug Administration in 1942. Robert C. Batterman and Clifton K. Himmelsbach, "Demerol-A New Synthetic Analgesic," J. Am. Med. Assoc., 1943, 122, 222-26
73. Methadone was initially called amidone by German chemists; information about this drug was released in the United States by the U.S. Department of Commerce just after the war. It was soon approved by the FDA under the trade name of Dolophine, manufactured by the pharmaceutical firm Eli Lilly and Company, which had been quick to synthesize and test the compound. C. C. Scott and K. K. Chen, "The Action of 1,1-diphenyl-1-(dimethylaminoisopropyl) butanone-2, a Potent Analgesic Agent," J. Pharmacol.Exp. Ther., 1946, 87, 63-71.
74. Batterman and Himmelsbach, "Demerol," 222.
75. Donald Slaughter and D. W. Munsell, "Some New Aspects of Morphine Action. Effects on Pain," J. Pharmacol. Exp. Ther., 1940, 68, 104-12
76. D. Slaughter and F. T. Wright, "A Modification of the Hardy-Wolff-Goodell Pain-Threshold Apparatus," Curr. Res. Anesth. Analg., 1944, 23, 115-19.
77. While CDA coordinating investigators were also, for the most part, nonclinicians who lacked authority and control over clinical testing, at least their access to clinical settings was facilitated by Committee connections.
78. John P. Swann, Academic Scientists and the Pharmaceutical Industry: Cooperative Research in Twentieth-Century America (Baltimore: Johns Hopkins University Press, 1988), 25.
79. Batterman and Himmelsbach, "Demerol," 222. R. H. K. Foster and A. J. Carman, "Studies in Analgesia: Piperidine Derivatives with Morphine-Like Activity," J. Pharmacol. Exp. Ther., 1947, 91, 195-209; Gross, Holland, and Schueler, "Human Studies."
80. C. C. Scott, E. B. Robbins, and K. K. Chen, "Pharmacologic Comparison of the Optical Isomers of Methadon," J. Pharmacol. Exp. Ther., 1948, 93, 282-86.
81. For Hoffmann-LaRoche funding, see Slaughter and Wright, "A Modification," 115-19; Gross et al., "Human Studies." For Whitehall Pharmacal, see Flinn and Chaikelis, "An Improved Instrument," 349-50. R. Sonnenschein was a fellow of Smith, Kline and French
82. R. R. Sonnenschein and A. C. Ivy, "Failure of Oral Antipyretic Drugs to Alter Normal Human Pain Thresholds," J. Pharmacol. Exp. Ther., 1949, 97, 308-13.
83. L. C. Miller, "A Critique;" K. K. Chen, "Physiological and Pharmacological Background Including Methods of Evaluation of Analgesic Agents," J. Am. Pharma. Assoc., 1949, 38, 51-55.
84. Miller, "A Critique," 34-50. The lucrative market for weaker over-the-counter analgesics may have made this a big disadvantage from the perspective of the pharmaceutical firms.
85. In late nineteenth- and early twentieth-century European and American psychology, trained subjects were not only tolerated but valued for their sharpened and standardized inner perceptions; see Ruth Benschop and Douwe Draaisma, "In Pursuit of Precision: The Calibration of Minds and Machines in Late Nineteenth Century Psychology," Ann. Sci., 2000, 57, 1-25
86. Deborah Coon, "Standardizing the Subject: Experimental Psychologists, Introspection, and the Quest for a Technoscientific Ideal," Tech. Cult., 1993, 34, 757-83.
87. Hardy, Pain Sensations, 82-83, explicitly calculated how training lowered the threshold of significance of data: 5-10% changes in pain intensity for trained subjects, incomparison with 20 percent or more in untrained subjects. The low number of subjects used by other researchers who acknowledged the importance of training suggests that they similarly viewed this as a measure of economy in subjects and time.
88. Sales pamphlet, Wolff Papers.
89. R. C. Batterman, "Clinical Effectiveness and Safety of a New Synthetic Analgesic Drug, Demerol," Arch. Intern. Med, 1943, 71, 345-56
90. Harry Gold, N. T. Kwit, and H. Otto, "The Xanthines (Theobromine and Aminophylline) in the Treatment of Cardiac Pain," J. Am. Med. Assoc., 1937, 108, 2173-79
91. E. M. Jellinek, "Clinical Tests on Comparative Effectiveness of Analgesic Drugs," Biometrics Bull., 1946, 2, 87-91
92. R. C. Batterman, "The Clinical Aspects of Evaluating Analgesics Agents," Yale J. Biol. Med., 1946, 18, 595-607.
93. "R. W. Bliss, Surgeon General to Dr. Weed (NRC), August 5, 1947," Bulletin of the Committee on Drug Addiction and Narcotics, 1947, 12.
94. William S. Stone to Henry K. Beecher, 5 January 1950, Box 22, Folder 15, Henry K. Beecher Papers (HMS c64), Francis A. Countway Library of Medicine, Harvard Medical School, Boston, Massachusetts (hereafter, Beecher Papers). Beecher's correspondence with the MRDB does not indicate, however, whether his sponsors specifically requested him to carry out this evaluation in a clinical setting. This funding may simply have been an extension of a larger grant for the Study of Sedatives provided to Beecher, on the basis of his expertise as an anesthesiologist and his military connections, to study other matters of military interest such as the use of barbiturates.
95. B. McPeek, "Pain," in "This Is No Humbug!" Reminiscences of the Department of Anesthesia at the Massachusetts General Hospital: A History, ed. R. Kitz et al. (Ashland, Ohio: Atlas Books, 2003).
96. In 1950, Beecher delivered an address to the American Society of Anaesthesiologists, which was published as H. K. Beecher, "Pain and Some of the Factors that Modify It," Anesthesiology, 1951, 12, 633-41
97. These areas of expertise are also highlighted in several editorials published in the journal Anesthesiology during the 1940s and 1950s: H. W. Haggard, "The Anesthetist in American Medicine," Anesthesiology 1940, 1, 1-12
98. Anon., "Postoperative Pain," Anesthesiology 1948, 9, 311-12
99. H. Boyd Stewart, "Editorial: Anesthesiology in the Practice of Medicine," Anesthesiology 1949, 10, 223-28
100. Anon., "The Anesthesiologist and the Public," Anesthesiology 1949, 10, 634-35
101. R. Charles Adams "Clinical Research in Anesthesiology," Anesthesiology 1950, 11, 178-84
102. Editorial: Clinical investigation," Anesthesiology 1951, 12, 114-18.
103. The CDA clinical studies, for example, were coordinated by the pharmacologist Nathan B. Eddy. The largest studies at Pondville Hospital were implemented by CDA researchers, initially by a nonclinician, and then by a clinician without a professional appointment at the site of study. Several of the clinical studies carried out in the 1940s were carried out by pharmacologists. See also Meldrum, "Each Patient."
104. Marks, The Progress of Experiment.
105. Although, as we have seen, some of these controls were recommended and sometimes implemented earlier.
106. Walton Van Winkle Jr., "Report to the Council," J. Am. Med. Assoc., 1949, 141, 1051, introduced Denton and Beecher, "New Analgesics. I."
107. Meldrum, "Each Patient."
108. At this time, drugs did not have to be proven effective in order to be approved by the FDA. Soon afterwards, however, the Durham-Humphrey Amendment Act of 1951 to the Food, Drug and Cosmetics Act of 1938 codified the categorization of prescription-only and over the counter drugs. For strong analgesics, the determination of addictiveness, which was a major component of the drug's safety, was closely tied to the minimal effective dose. Getting a strong analgesic approved as an over-the-counter drug had significant commercial implications for pharmaceutical firms, as shown by the case of dextropropoxyphene (Darvon). See Meldrum, "Departures from the Design."
109. Beecher's research continued to be funded even after CDAN's industry sponsors began to complain about its lack of immediate practical application and expressed a desire to initiate a re-exploration of the more economical laboratory methods of analgesic testing. N. B. Eddy to Starr, 11 May 1953, Box 2: General, 1947-June 1959: CDAN: Division of Medicine: NASA (hereafter CDAN-NASA).
110. "Minutes of Conference with Representatives of Drug Manufacturers, July 1, 1949," Box 1: Minutes, July 1949 Conference with Representatives of Drug Manufacturers, CDAN-NASA.
111. A significant portion of these grants went to technicians' (observers) salaries. For example, in a 1952 grant application, Beecher requested $5,980 for this purpose out of a total of $16,679 (part of this budget was for a separate study of side effects, so the salary's proportion of the cost of clinical trial work was even higher). See H. K. Beecher, "Annual Report and Application for Renewal of Support to the Committee on Narcotics and Drug Addiction of the National Research Council, 21 January 1952," Bulletin of the Committee on Drug Addiction and Narcotics, 1952, 225.
112. Beecher, "Annual Report," 222-23, said "the aid of a top level statistician is essential. Professor Mosteller has become interested in this problem and if an application is approved will be available for this aspect of the work." Harry Marks emphasizes the role of alliances between clinicians and statisticians in the postwar emergence of clinical trials, and draws attention to the mutually beneficial nature of this alliance by describing it as a "gift relationship," The Progress of Experiment, 148-55.
113. Beecher, "A Method for Quantifying."
114. H. K. Beecher, "A Study of the Placebo Response," Bulletin of the Committee on Drug Addiction and Narcotics, 1953, 377.
115. Beecher, "Experimental Pharmacology."
116. "Report of Ad Hoc Group to Consider Proposed Clinical Investigation of Analgesic Drugs in VA Hospitals," Bulletin of the Committee on Drug Addiction and Narcotics, 1958, 1896-98.
117. Marks, The Progress of Experiment.
118. David Healy, The Antidepressant Era (Cambridge, Massachusetts: Harvard University Press, 1997), 95-96.
119. H. K. Beecher, "Limiting Factors in Experimental Pain," J. Chronic Dis., 1956, 4, 11-21.
120. Keats, Beecher, and Mosteller, "Measurement of Pathological."
121. Meldrum, "Each Patient His Own Control"; Meldrum, "Departures from the Design," 287-88.
122. Though the specific explanation given by Beecher was later replaced by reference to the action of endogenous opiates (such as endorphins), this study would often be cited by researchers who sought to reform conceptions of pain by pointing out that sensoryphysiological events were only a small, sometimes insignificant part of the total subjective pain experience.
123. For example, Malmo et al., "Standardized Pain"; Chapman et al., "Measurements of Pain."
124. For example, Thomas H. Holmes and Harold G. Wolff, "Life Situations, Emotions and Backache," Res. Publ. Assoc. Res. Nerv. Ment. Dis., 1950, 29, 750-72
125. Leo Rangell, "Psychiatric Aspects of Pain," Psychosom. Med., 1953, 35, 22-37. This interest is even more evident in publications from the later 1950s and 1960s.
126. Baszanger, Inventing Pain Medicine, describes how Bonica defined a new clinical entity, chronic pain, which was characterized not only by its duration but by its psychological components, which developed over time even if the pain had a physical origin. This type of pain affected the whole person and thus required a multidisciplinary clinical approach in a team including psychologists and psychiatrists. See also William K. Livingston, Pain Mechanisms: A Physiologic Interpretation of Causalgia and Its Related States (New York: Macmillan, 1944); John J. Bonica, The Management of Pain with Special Emphasis on the Use of Analgesic Block in Diagnosis, Prognosis, and Therapy (Philadelphia:
127. Lea & Febiger, 1953); Ronald Melzack and Patrick Wall, "Pain Mechanisms: A New Theory," Science, 1965, 150, 971-79.
128. E. Williams, "A Quantitative Measure of Analgesia (Summary of Work Done at Lexington in Past Year, November 12, 1938
129. L. Kolb to W. C. White, 12 November 1938, Projects: Development of Nonaddictive Analgesics: Clinical Studies: PHS Hospital: Lexington General, CDA-NASA.
130. Louis Lasagna, "The Lawfulness of Clinical Pain," Fed. Proc., 1961, 20, 309.
131. The broader diffusion of the analgesic clinical trial relied on CDAN sponsorship and networks of communication; the first researchers who took up the method worked directly with Beecher and/or were funded by CDAN and participated in its meetings.
132. Beecher, "Pain: One Mystery Solved," Science, 1966, 151, 840-41.