Highlights
- •Desmetramadol delivers the active metabolite of tramadol.
- •P450 enzyme inhibition made participants metabolically deficient.
- •Tramadol lost its analgesic efficacy in metabolically deficient participants.
- •Desmetramadol preserved its efficacy in metabolically deficient participants.
- •Desmetramadol and tramadol had the same safety profile.
Abstract
ClinicalTrials.gov registrations
Perspective
Graphical abstract

Key words

- Singla N
- Minkowitz HS
- Soergel DG
- Burt DA
- Subach RA
- Salamea MY
- Fossler MJ
- Skobieranda F
- Soergel DG
- Subach RA
- Burnham N
- Lark MW
- James IE
- Sadler BM
- Skobieranda F
- Violin JD
- Webster LR
U.S. National Library of Medicine: TOXNET. Toxicology Data Network. Available at: https://toxnet.nlm.nih.gov. Accessed May, 15, 2019
- Crews KR
- Gaedigk A
- Dunnenberger HM
- Leeder JS
- Klein TE
- Caudle KE
- Haidar CE
- Shen DD
- Callaghan JT
- Sadhasivam S
- Prows CA
- Kharasch ED
- Skaar TC
Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update.
Drug Enforcement Administration: Diversion Control Division. Drug & Chemical Evaluation Section: Tramadol (Trade Names: Ultram®, Ultracet®). Available at: www.deadiversion.usdoj.gov/drug_chem_info/tramadol.pdf. Accessed November, 5, 2018
Methods
Study Design

End Points and Formal Study Hypothesis
Trial A
Trial B
Participants
Key Inclusion Criteria | Key Exclusion Criteria |
---|---|
Healthy male and female (trial B) adults ≤55 years old with normal blood pressure, pulse, and respiration Tolerance to cold-induced pain of ≥20 and ≤120 seconds Negative urine for substances of abuse Normal or intermediate CYP2D6 metabolizer (trial B) Adequate hematologic and liver function per predefined limits Cockcroft-Gault glomerular filtration rate of ≥60 mL/min and urinalysis with ≤+1 glucose, +1 ketones, and +1 protein Body mass index of 18.0–32 kg/m2 If female of childbearing potential, must use adequate contraception Electrocardiogram without clinically significant changes Negative serology for HIV, hepatitis B surface antigen, and hepatitis C virus antibody | History of seizures, epilepsy, or recognized increase risk of seizure History of cirrhosis or laboratory evidence of liver disease Known or suspected alcohol or drug abuse within the past 6 months Inhibitors of monoamine oxidase, serotonin and/or norepinephrine reuptake, and other medications or supplements known to induce or inhibit drug metabolism or that may affect the serotonergic neurotransmitter system Ethanol, grapefruit, grapefruit-related citrus fruits (eg, Seville oranges, pomelos), grapefruit-related juices or other new medication Pregnant or breast feeding (trial B) |
Designation of CYP2D6 Phenotype
- Crews KR
- Gaedigk A
- Dunnenberger HM
- Leeder JS
- Klein TE
- Caudle KE
- Haidar CE
- Shen DD
- Callaghan JT
- Sadhasivam S
- Prows CA
- Kharasch ED
- Skaar TC
Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update.
Assessments
Steady-State Pharmacokinetics
Pupillometry
Abuse Liability
- Comer SD
- Zacny JP
- Dworkin RH
- Turk DC
- Bigelow GE
- Foltin RW
- Jasinski DR
- Sellers EM
- Adams EH
- Balster R
- Burke LB
- Cerny I
- Colucci RD
- Cone E
- Cowan P
- Farrar JT
- Haddox JD
- Haythornthwaite JA
- Hertz S
- Jay GW
- Johanson CE
- Junor R
- Katz NP
- Klein M
- Kopecky EA
- Leiderman DB
- McDermott MP
- O'Brien C
- O'Connor AB
- Palmer PP
- Raja SN
- Rappaport BA
- Rauschkolb C
- Rowbotham MC
- Sampaio C
- Setnik B
- Sokolowska M
- Stauffer JW
- Walsh SL
Analgesia
Safety and Tolerability
FDA: Guidance for Industry: Toxicity grading scale for healthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials. Available at: www.fda.gov/downloads/BiologicsBloodVaccines/ucm091977. Accessed October 30, 2018
Statistical and Computational Methods
- Hagelberg NM
- Saarikoski T
- Saari TI
- Neuvonen M
- Neuvonen PJ
- Turpeinen M
- Scheinin M
- Laine K
- Olkkola KT
FDA: FDA Guidance for Industry: Statistical approaches to establishing bioequivalence. Available at: www.fda.gov/downloads/drugs/guidances/ucm070244.pdf. Accessed October 30, 2018
Results
Participant Disposition and Demographics

Characteristics | Trial A (n = 43) | Trial B (n = 60) |
---|---|---|
Age, years | 28.4 ± 8.0 | 28.0 ± 6.8 |
Age range, years | ||
Minimum | 21 | 18 |
Maximum | 53 | 45 |
Sex | ||
Male | 43 (100) | 42 (70) |
Female | 0 (0) | 18 (30) |
Race | ||
Caucasian | 39 (91) | 56 (93) |
Asian | 3 (7) | 0 (0) |
Black or African American | 0 (0) | 3 (5) |
American Indian or Alaska Native | 1 (2) | 1 (2) |
Ethnicity | ||
Hispanic or Latino | 6 (14) | 7 (12) |
Not Hispanic or Latino | 37 (86) | 53 (88) |
BMI, kg/m2 | 25.5 ± 3.1 | 24.8 ± 3.4 |
BMI range, kg/m2 | ||
Minimum | 19.5 | 18.9 |
Maximum | 31.8 | 31.7 |
CYP2D6 activity score, phenotype | ||
.0, Poor metabolizer | 1 (2) | 0 (0) |
.5, Intermediate metabolizer | 0 (0) | 3 (5) |
1.0, Intermediate metabolizer | 17 (41) | 19 (32) |
1.5, Normal metabolizer | 7 (17) | 9 (15) |
2.0, Normal metabolizer | 16 (38) | 29 (48) |
3.0, Ultrarapid metabolizer | 1 (2) | 0 (0) |
Steady-State Pharmacokinetics

Trial A (n = 43) | Trial B (n = 60) | |||
---|---|---|---|---|
Analyte | Tramadol | Desmetramadol | Tramadol | Desmetramadol |
(+)-M1 | ||||
Cssmin, ng/mL, M (SD) | 28 (7) | 26 (6) | 11 (6) | 38 (9) |
90% CI | .85–1.08 | 3.4–4.3 | ||
P value | <.001 | |||
Cssmax, ng/mL, M (SD) | 37 (10) | 36 (10) | 14 (8) | 51 (11) |
90% CI | .88–1.13 | 3.4–4.3 | ||
P value | <.001 | |||
t1/2, h, M (SD) | 18 (39) | 8 (6) | ||
P value | .065 | |||
(-)-M1 | ||||
Cssmin, ng/mL, M (SD) | 30 (6) | 21 (5) | 25 (7) | 25 (8) |
90% CI | .69–.76 | .95–1.09 | ||
P value | .64 | |||
Cssmax, ng/mL, M (SD) | 42 (9) | 30 (9) | 35 (10) | 35 (10) |
90% CI | .67–.76 | .93–1.07 | ||
P value | .79 | |||
t1/2, h, M (SD) | 12 (8) | 7 (5) | ||
P value | <.001 | |||
(+)-tramadol | ||||
Cssmin, ng/mL, M (SD) | 85 (33) | ND | 183 (49) | ND |
Cssmax, ng/mL, M (SD) | 143 (36) | ND | 295 (62) | ND |
t1/2, h, M (SD) | 8.6 (2.5) | ND | ||
(-)-tramadol | ||||
Cssmin, ng/mL, M (SD) | 68 (27) | ND | 140 (41) | ND |
Cssmax, ng/mL, M (SD) | 122 (32) | ND | 242 (56) | ND |
t1/2, h, M (SD) | 7.2 (2.3) | ND | ||
Paroxetine, ng/mL, M (SD) | NA | NA | 11 (8) | 12 (9) |
Pupillometry and Abuse Measures
Trial A (n = 43) | |||
---|---|---|---|
Placebo | Tramadol | Desmetramadol | |
Pupil diameter, mm, M (SD) | |||
Predose | 6.1 (.9) | 6.1 (.9) | 6.0 (1.1) |
After seventh dose | 6.2 (1.0) | 5.5 (1.1) | 5.1 (1.2) |
P value vs placebo | <.0001 | <.0001 | |
Abuse Measures, 0–100 mm, M (SD) | |||
Drug liking–disliking | 49 (14) | 48 (15) | 47 (25) |
P value vs placebo | NS | NS | |
Take drug again | 49 (19) | 47 (18) | 43 (26) |
P value vs placebo | NS | NS | |
Strength of drug effect | 12 (18) | 32 (29) | 29 (28) |
P value vs placebo | <.0001 | .0004 |
Analgesia

Safety and Tolerability
AEs
Trial A (n = 43; M = 43) | Trial B (n = 60; M = 42, F = 18) | |||||
---|---|---|---|---|---|---|
Event, n (%) | Placebo | Tramadol | Desmetramadol | Placebo | Tramadol | Desmetramadol |
All AEs | 10 (24) | 20 (49) | 19 (44) | 16 (27) | 30 (50) | 40 (67) |
Specified AEs | ||||||
Nausea | 3 (7) | 5 (12) | 8 (19) | 7 (12) | 8 (13) | 16 (27) |
M | 3 (7) | 5 (12) | 8 (19) | 4 (10) | 6 (14) | 11 (26) |
F | — | — | — | 3 (17) | 2 (11) | 5 (28) |
Dizziness | 1 (2) | 5 (12) | 6 (14) | 1 (2) | 8 (13) | 12 (20) |
Male | 1 (2) | 5 (12) | 6 (14) | 1 (2) | 4 (10) | 7 (17) |
Female | — | — | — | 0 (0) | 4 (22) | 5 (28) |
Somnolence | 0 (0) | 2 (5) | 3 (7) | 2 (3) | 4 (7) | 10 (17) |
Male | 0 (0) | 2 (5) | 3 (7) | 1 (2) | 2 (5) | 4 (10) |
Female | — | — | — | 1 (6) | 2 (11) | 6 (33) |
Headache | 0 (0) | 7 (17) | 3 (7) | 3 (5) | 6 (10) | 10 (17) |
Male | 0 (0) | 7 (17) | 3 (7) | 0 (0) | 0 (0) | 4 (10) |
Female | — | — | — | 3 (17) | 6 (33) | 6 (33) |
Vomiting | 0 (0) | 1 (2) | 1 (2) | 1 (2) | 2 (3) | 9 (15) |
Male | 0 (0) | 1 (2) | 1 (2) | 1 (2) | 2 (5) | 6 (14) |
Female | — | — | — | 0 (0) | 0 (0) | 3 (17) |
Presyncope | 0 (0) | 0 (0) | 0 (0) | 1 (2) | 6 (10) | |
Male | 1 (2) | 0 (0) | 0 (0) | 0 (0) | 1 (2) | 3 (7) |
Female | — | — | — | 0 (0) | 0 (0) | 3 (17) |
Pruritus | 0 (0) | 4 (10) | 3 (7) | 1 (2) | 1 (2) | 4 (7) |
Male | 0 (0) | 4 (10) | 3 (7) | 0 (0) | 0 (0) | 1 (2) |
Female | — | — | — | 1 (6) | 1 (6) | 3 (17) |
Spasticity | 0 (0) | 1 (2) | 0 (0) | 0 (0) | 3 (5) | 3 (5) |
Male | 0 (0) | 1 (2) | 0 (0) | 0 (0) | 3 (7) | 3 (7) |
Female | — | — | — | 0 (0) | 0 (0) | 0 (0) |
Feel abnormal | 0 (0) | 1 (2) | 0 (0) | 0 (0) | 2 (3) | 3 (5) |
Male | 0 (0) | 1 (2) | 0 (0) | 0 (0) | 2 (5) | 2 (5) |
Female | — | — | — | 0 (0) | 0 (0) | 1 (6) |
Feel hot | 0 (0) | 0 (0) | 0 (0) | 1 (2) | 0 (0) | 3 (5) |
Male | 0 (0) | 0 (0) | 0 (0) | 1 (2) | 0 (0) | 2 (5) |
Female | — | — | — | 0 (0) | 0 (0) | 1 (6) |
Euphoria | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (2) | 2 (3) |
Male | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (2) | 1 (2) |
Female | — | — | — | 0 (0) | 0 (0) | 1 (6) |
Sweating | 0 (0) | 0 (0) | 0 (0) | 1 (2) | 1 (2) | 2 (3) |
Male | 0 (0) | 0 (0) | 0 (0) | 1 (2) | 1 (2) | 2 (5) |
Female | — | — | — | 0 (0) | 0 (0) | 0 (0) |
Severe AEs | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
Deaths | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
Respiration and Other Vital Signs

Tramadol Versus Placebo | Desmetramadol Versus Placebo | Desmetramadol Versus Tramadol | |
---|---|---|---|
Trial A, n = 43 | |||
Respiratory rate, min−1, MPD (SD) | −.24 (.97) NS | −.14 (.87) NS | .11 (.91) NS |
Trial B, n = 60 | |||
Respiratory rate, min−1, MPD (SD) | −.34 (.99) P = .004 | −.30 (.90) P = .012 | .05 (.85) P = .345 |
Discussion
Key Findings and Clinical Significance
Drug Enforcement Administration: Diversion Control Division. Drug & Chemical Evaluation Section: Tramadol (Trade Names: Ultram®, Ultracet®). Available at: www.deadiversion.usdoj.gov/drug_chem_info/tramadol.pdf. Accessed November, 5, 2018
- Crews KR
- Gaedigk A
- Dunnenberger HM
- Leeder JS
- Klein TE
- Caudle KE
- Haidar CE
- Shen DD
- Callaghan JT
- Sadhasivam S
- Prows CA
- Kharasch ED
- Skaar TC
Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update.
Pharmacologic Underpinnings
Trial A and Trial B End Points

Role of Metabolism in Desmetramadol Elimination
- Hagelberg NM
- Saarikoski T
- Saari TI
- Neuvonen M
- Neuvonen PJ
- Turpeinen M
- Scheinin M
- Laine K
- Olkkola KT
- Hagelberg NM
- Saarikoski T
- Saari TI
- Neuvonen M
- Neuvonen PJ
- Turpeinen M
- Scheinin M
- Laine K
- Olkkola KT
- Soetebeer UB
- Schierenberg MO
- Schulz H
- Andresen P
- Blaschke G
Seizures and Serotonin Syndrome
Impact on Respiration
- Singla N
- Minkowitz HS
- Soergel DG
- Burt DA
- Subach RA
- Salamea MY
- Fossler MJ
- Skobieranda F
- Soergel DG
- Subach RA
- Burnham N
- Lark MW
- James IE
- Sadler BM
- Skobieranda F
- Violin JD
- Webster LR
Abuse Potential
Basis for the recommendation to schedule tramadol in schedule IV of the Controlled Substances Act.
Basis for the recommendation to schedule tramadol in schedule IV of the Controlled Substances Act.
- Comer SD
- Zacny JP
- Dworkin RH
- Turk DC
- Bigelow GE
- Foltin RW
- Jasinski DR
- Sellers EM
- Adams EH
- Balster R
- Burke LB
- Cerny I
- Colucci RD
- Cone E
- Cowan P
- Farrar JT
- Haddox JD
- Haythornthwaite JA
- Hertz S
- Jay GW
- Johanson CE
- Junor R
- Katz NP
- Klein M
- Kopecky EA
- Leiderman DB
- McDermott MP
- O'Brien C
- O'Connor AB
- Palmer PP
- Raja SN
- Rappaport BA
- Rauschkolb C
- Rowbotham MC
- Sampaio C
- Setnik B
- Sokolowska M
- Stauffer JW
- Walsh SL
Abuse Measure Versus Placebo | |||||
---|---|---|---|---|---|
Opioid, Oral Route | n | Drug Liking-Disliking | Take Drug Again | Strength of Drug Effect | Study |
Drug abusers | |||||
Morphine | |||||
25 mg | 12 | 8 | 6 | 35 | Zacny 2005 |
Oxycodone | |||||
15 mg | 9 | 21 | 35 | 43 | Comer 2010 |
30 mg | 9 | 19 | 33 | 50 | Comer 2010 |
Hydromorphone | |||||
4 mg | 8 | 29 | — | 19 | Duke 2011 |
8 mg | 8 | 44 | — | 32 | Duke 2011 |
Tramadol | |||||
50 mg | 22 | 3 | 5 | 5 | Zacny 2005 |
100 mg | 22 | 10 | 9 | 20 | Zacny 2005 |
50 mg | 8 | 1 | — | 0 | Duke 2011 |
100 mg | 8 | 6 | — | 4 | Duke 2011 |
200 mg | 8 | 15 | — | 19 | Duke 2011 |
400 mg | 8 | 24 | — | 19 | Duke 2011 |
Non-drug abusers | |||||
Morphine | |||||
30 mg | 20 | 12 | 12 | 28 | Zacny 2008 |
40 mg | 18 | 12 | 12 | 33 | Zacny 2003 |
Oxycodone | |||||
10 mg | 18 | 13 | 15 | 30 | Zacny 2003 |
15 mg | 9 | 19 | 18 | 45 | Comer 2010 |
20 mg | 18 | 20 | 21 | 48 | Zacny 2003 |
20 mg | 20 | 16 | 17 | 53 | Zacny 2008 |
30 mg | 9 | 18 | 15 | 53 | Comer 2010 |
30 mg | 18 | 21 | 20 | 58 | Zacny 2003 |
Hydrocodone | |||||
15 mg | 20 | 4 | 4 | 33 | Zacny 2009 |
30 mg | 20 | 8 | 6 | 50 | Zacny 2009 |
Tramadol | |||||
50 mg | 43 | −1 | −2 | 20 | This study |
Desmetramadol | |||||
20 mg | 43 | −2 | −6 | 17 | This study |
Conclusions
Acknowledgments
Appendix. Supplementary data
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Supported by a National Institute on Drug Abuse grant DA027304 to Syntrix. Syntrix developed the protocols in conjunction with the clinical investigators and provided the study drug. The article was prepared by Syntrix. The authors are fully responsible for all content and editorial decisions for this report. There was no editorial support from other parties. J.A.Z. was an employee of Syntrix during the execution of the reported study, and an owner of Syntrix stock. S.L.S. and L.R.W. were employees of PRA Health Sciences during the conduct of the study. M.S.J was an employee of DF/Net Research during the study and its analysis and received standard compensation. A.D.S, D.Y.M. and S.J.K. were employees of Syntrix during the execution of the study and its analysis.
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