Titration of Cebranopadol

1. A method of treating pain in a patient in need of such treatment, said method comprising administering Cebranopadol according to an administration regimen comprising:

(i) a first administration interval, which lasts for at least 2 consecutive days, wherein a first daily dose of Cebranopadol is administered on every day of the first administration interval, wherein the first daily dose of Cebranopadol is in an amount that is expected to be subtherapeutic for the patient;

(ii) a second administration interval, which lasts for at least 2 consecutive days and directly follows the first administration interval without interruption, wherein a second daily dose of Cebranopadol is administered on every day of the second administration interval; and

(iii) a third administration interval, which lasts for at least 2 consecutive days and directly follows the second administration interval without interruption, wherein a third daily dose of Cebranopadol is administered on every day of the third administration interval;

wherein the first daily dose of Cebranopadol is lower than the second daily dose of Cebranopadol; and

wherein the second daily dose of Cebranopadol is lower than the third daily dose of Cebranopadol.

2. The method according to claim 1 , wherein

the first daily dose of Cebranopadol is less than 200 μg; and/or

the first administration interval lasts for at least 4 consecutive days.

3. The method according to claim 1 , wherein the first daily dose of Cebranopadol is within the range of from 30 to 70 wt.-% of the second daily dose of Cebranopadol.

4. The method according to claim 1 , wherein

the first daily dose of Cebranopadol is within the range of from 10 to 190 μg; and/or

the second daily dose of Cebranopadol is within the range of from 110 to 290 μg.

5. The method according to claim 1 , wherein the first daily dose of Cebranopadol is within the range of from 5 to 45 wt.-% of the third daily dose of Cebranopadol and wherein the second daily dose of Cebranopadol is within the range of from 30 to 70 wt.-% of the third daily dose of Cebranopadol.

6. The method according to claim 1 , wherein the third daily dose of Cebranopadol is within the range of from 310 to 490 μg.

7. The method according to claim 1 , wherein the administration regimen additionally comprises

(iv) a fourth administration interval, which lasts for at least 2 consecutive days and directly follows the third administration interval without interruption, wherein a fourth daily dose of Cebranopadol is administered on every day of the fourth administration interval;

wherein the third daily dose of Cebranopadol is lower than the fourth daily dose of Cebranopadol.

8. The method according to claim 7 , wherein the first daily dose of Cebranopadol is within the range of from 5 to 30 wt.-% of the fourth daily dose of Cebranopadol, wherein the second daily dose of Cebranopadol is within the range of from 15 to 50 wt.-% of the fourth daily dose of Cebranopadol, and wherein the third daily dose of Cebranopadol is within the range of from 50 to 75 wt.-% of the fourth daily dose of Cebranopadol.

9. The method according to claim 7 , wherein the fourth daily dose of Cebranopadol is within the range of from 510 to 690 μg.

10. The method according to claim 1 , wherein the first daily dose of Cebranopadol, the second daily dose of Cebranopadol, the third daily dose of Cebranopadol, and/or an optional fourth daily dose of Cebranopadol independently of one another are administered orally.

11. The method according to claim 1 , wherein the first daily dose of Cebranopadol, the second daily dose of Cebranopadol, the third daily dose of Cebranopadol, and/or an optional fourth daily dose of Cebranopadol independently of one another are administered once daily (sid).

12. The method according to claim 1 , wherein

(i) the first administration interval, the second administration interval, the third administration interval, and/or an optional fourth administration interval, and/or an optional fifth administration interval, and/or an optional sixth administration interval, and/or an optional seventh administration interval independently of one another last for 5 to 7 consecutive days; or

(ii) the first administration interval, the second administration interval, the third administration interval, and/or an optional fourth administration interval, and/or an optional fifth administration interval, and/or an optional sixth administration interval, and/or an optional seventh administration interval independently of one another last for 2 to 4 consecutive days.

13. The method according to claim 1 , wherein the administration regimen comprises

(i) a first administration interval, which lasts for at least α consecutive days, wherein a first daily dose of Cebranopadol is orally administered on every day of the first administration interval;

(ii) a second administration interval, which lasts for at least β consecutive days and directly follows the first administration interval without interruption, wherein a second daily dose of Cebranopadol is orally administered on every day of the second administration interval;

(iii) a third administration interval, which lasts for at least γ consecutive days and directly follows the second administration interval without interruption, wherein a third daily dose of Cebranopadol is orally administered on every day of the third administration interval; and

(iv) optionally, a fourth administration interval, which lasts for at least δ consecutive days and directly follows the third administration interval without interruption, wherein a fourth daily dose of Cebranopadol is orally administered on every day of the fourth administration interval;

(v) optionally, a fifth administration interval, which lasts for at least ε consecutive days and directly follows the fourth administration interval without interruption, wherein a fifth daily dose of Cebranopadol is orally administered on every day of the fifth administration interval; and

(vi) optionally, a sixth administration interval, which lasts for at least ϕ consecutive days and directly follows the fifth administration interval without interruption, wherein a sixth daily dose of Cebranopadol is orally administered on every day of the sixth administration interval; and

(vii) optionally, a seventh administration interval, which lasts for at least χ consecutive days and directly follows the sixth administration interval without interruption, wherein a seventh daily dose of Cebranopadol is orally administered on every day of the seventh administration interval;

and satisfies any of the following requirements A 1 to C 3 :

A 1

A 2

A 10

A 12

A 20

A 21

first daily dose [μg]

100 ± 80

100 ± 80

100 ± 50

100 ± 50

100 ± 20

100 ± 20

α [days]

≥3

≥4

≥5

 7 ± 3

 6 ± 2

 6 ± 1

second daily dose [μg]

200 ± 80

200 ± 80

200 ± 50

200 ± 50

200 ± 20

200 ± 20

β [days]

≥3

≥4

≥5

 7 ± 3

 6 ± 2

 6 ± 1

third daily dose [μg]

400 ± 80

400 ± 80

400 ± 50

400 ± 50

400 ± 20

400 ± 20

γ [days]

≥3

≥4

≥5

 7 ± 3

 6 ± 2

 6 ± 1

B 1

B 2

B 10

B 12

B 20

B 21

first daily dose [μg]

100 ± 80

100 ± 80

100 ± 50

100 ± 50

100 ± 20

100 ± 20

α [days]

≥3

≥4

≥5

 7 ± 3

 6 ± 2

 6 ± 1

second daily dose [μg]

200 ± 80

200 ± 80

200 ± 50

200 ± 50

200 ± 20

200 ± 20

β [days]

≥3

≥4

≥5

 7 ± 3

 6 ± 2

 6 ± 1

third daily dose [μg]

400 ± 80

400 ± 80

400 ± 50

400 ± 50

400 ± 20

400 ± 20

γ [days]

≥3

≥4

≥5

 7 ± 3

 6 ± 2

 6 ± 1

fourth daily dose [μg]

600 ± 80

600 ± 80

600 ± 50

600 ± 50

600 ± 20

600 ± 20

δ [days]

≥3

≥4

≥5

 7 ± 3

 6 ± 2

 6 ± 1

C 1

C 2

C 3

first daily dose [μg]

50 ± 40

50 ± 40

50 ± 40

α [days]

≥2

≥3

3 ± 1

second daily dose [μg]

100 ± 80

100 ± 80

100 ± 80 

β [days]

≥2

≥3

3 ± 1

third daily dose [μg]

200 ± 80

200 ± 80

200 ± 80 

γ [days]

≥2

≥3

3 ± 1

fourth daily dose [μg]

300 ± 80

300 ± 80

300 ± 80 

δ [days]

≥2

≥3

3 ± 1

fifth daily dose [μg]

400 ± 80

400 ± 80

400 ± 80 

ε [days]

≥2

≥3

3 ± 1

sixth daily dose [μg]

500 ± 80

500 ± 80

500 ± 80 

ϕ [days]

≥2

≥3

3 ± 1

seventh daily dose [μg]

600 ± 80

600 ± 80

600 ± 80 

χ [days]

≥2

≥3

3 ± 1

14. The method according to claim 1 , wherein the pain is

acute pain or chronic pain; and/or

nociceptive pain or neuropathic pain; and/or

postoperative pain, malignant pain, and/or inflammatory pain.

15. A method of reducing side effects associated with treatment for pain, said method comprising administering Cebranopadol according to an administration regimen comprising:

(i) a first administration interval, which lasts for at least 2 consecutive days, wherein a first daily dose of Cebranopadol is administered on every day of the first administration interval, wherein the first daily dose of Cebranopadol is in an amount that is expected to be subtherapeutic for the patient;

(ii) a second administration interval, which lasts for at least 2 consecutive days and directly follows the first administration interval without interruption, wherein a second daily dose of Cebranopadol is administered on every day of the second administration interval; and

(iii) an optional third administration interval, which lasts for at least 2 consecutive days and directly follows the second administration interval without interruption, wherein a third daily dose of Cebranopadol is administered on every day of the third administration interval;

wherein the first daily dose of Cebranopadol is lower than the second daily dose of Cebranopadol; and

wherein the second daily dose of Cebranopadol is lower than the optional third daily dose of Cebranopadol.

16. The method according to claim 15 , wherein

the first daily dose of Cebranopadol is less than 200 μg; and/or

the first administration interval lasts for at least 4 consecutive days.

17. The method according to claim 15 , wherein the first daily dose of Cebranopadol is within the range of from 30 to 70 wt.-% of the second daily dose of Cebranopadol.

18. The method according to claim 15 , wherein

the first daily dose of Cebranopadol is within the range of from 60 to 140 μg; and/or

the second daily dose of Cebranopadol is within the range of from 160 to 240 μg.

19. The method according to claim 15 , wherein the first daily dose of Cebranopadol is within the range of from 5 to 45 wt.-% of the third daily dose of Cebranopadol and wherein the second daily dose of Cebranopadol is within the range of from 30 to 70 wt.-% of the third daily dose of Cebranopadol.

20. The method according to claim 15 , wherein the third daily dose of Cebranopadol is 95-105 μg greater than the second daily dose of Cebranopadol.

21. The method according to claim 15 , wherein the administration regimen additionally comprises

(iv) a fourth administration interval, which lasts for at least 2 consecutive days and directly follows the third administration interval without interruption, wherein a fourth daily dose of Cebranopadol is administered on every day of the fourth administration interval;

wherein the third daily dose of Cebranopadol is lower than the fourth daily dose of Cebranopadol.

22. The method according to claim 21 , wherein the first daily dose of Cebranopadol is within the range of from 5 to 30 wt.-% of the fourth daily dose of Cebranopadol, wherein the second daily dose of Cebranopadol is within the range of from 15 to 50 wt.-% of the fourth daily dose of Cebranopadol, and wherein the third daily dose of Cebranopadol is within the range of from 55 to 80 wt.-% of fourth daily dose of Cebranopadol.

23. The method according to claim 21 , wherein the fourth daily dose of Cebranopadol is 95-105 μg greater than the third daily dose of Cebranopadol.

24. The method according to claim 21 , wherein the first daily dose of Cebranopadol, the second daily dose of Cebranopadol, the third daily dose of Cebranopadol, and/or the fourth daily dose of Cebranopadol independently of one another are administered orally.

25. The method according to claim 21 , wherein the first daily dose of Cebranopadol, the second daily dose of Cebranopadol, the third daily dose of Cebranopadol, and/or the fourth daily dose of Cebranopadol independently of one another are administered once daily (sid).

26. The method according to claim 15 , wherein

(i) the first administration interval, the second administration interval, the optional third administration interval, and/or an optional fourth administration interval, and/or an optional fifth administration interval, and/or an optional sixth administration interval, and/or an optional seventh administration interval independently of one another last for 5 to 7 consecutive days; or

(ii) the first administration interval, the second administration interval, and/or an optional third administration interval, and/or an optional fourth administration interval, and/or an optional fifth administration interval, and/or an optional sixth administration interval, and/or an optional seventh administration interval independently of one another last for 2 to 4 consecutive days.

27. The method according to claim 15 , wherein the administration regimen comprises

(i) a first administration interval, which lasts for at least α consecutive days, wherein a first daily dose of Cebranopadol is orally administered on every day of the first administration interval; and

(ii) a second administration interval, which lasts for at least β consecutive days and directly follows the first administration interval without interruption, wherein a second daily dose of Cebranopadol is orally administered on every day of the second administration interval;

and satisfies any of the following requirements A 1 to C 3 :

A 1

A 2

A 10

A 12

A 20

A 21

first daily

100 ± 80

100 ± 80

100 ± 50

100 ± 50

100 ± 20

100 ± 20

dose [μg]

α [days]

≥3

≥4

≥5

 7 ± 3

 6 ± 2

 6 ± 1

second daily

200 ± 80

200 ± 80

200 ± 50

200 ± 50

200 ± 20

200 ± 20

dose [μg]

β [days]

≥3

≥4

≥5

 7 ± 3

 6 ± 2

 6 ± 1

B 1

B 2

B 10

B 12

B 20

B 21

first daily

100 ± 80

100 ± 80

100 ± 50

100 ± 50

100 ± 20

100 ± 20

dose [μg]

α [days]

≥3

≥4

≥5

 7 ± 3

 6 ± 2

 6 ± 1

second daily

200 ± 80

200 ± 80

200 ± 50

200 ± 50

200 ± 20

200 ± 20

dose [μg]

β [days]

≥3

≥4

≥5

 7 ± 3

 6 ± 2

 6 ± 1

δ [days]

≥3

≥4

≥5

 7 ± 3

 6 ± 2

 6 ± 1

C 1

C 2

C 3

first daily dose [μg]

100 ± 20

100 ± 20

100 ± 20

α [days]

≥4

≥5

≥6

second daily dose [μg]

200 ± 20

200 ± 20

200 ± 20

β [days]

≥4

≥5

≥6

28. The method according to claim 15 , wherein the pain is

acute pain or chronic pain; and/or

nociceptive pain or neuropathic pain; and/or

postoperative pain, malignant pain, and/or inflammatory pain.

29. The method according to claim 15 , wherein the administration regimen comprises

(i) a first administration interval, which lasts for at least 4 consecutive days, wherein a first daily dose of 100 μg of Cebranopadol is orally administered on every day of the first administration interval; and

(ii) a second administration interval, which lasts for at least 4 consecutive days and directly follows the first administration interval without interruption, wherein a second daily dose of 200 μg of Cebranopadol is orally administered on every day of the second administration interval.

30. The method according to claim 29 , further comprising a third administration interval, which lasts for at least 4 consecutive days and directly follows the second administration interval without interruption, wherein a third daily dose of 300 μg of Cebranopadol is orally administered on every day of the third administration interval.

31. The method according to claim 29 , wherein each administration interval lasts for at least 5 consecutive days.

32. The method according to claim 15 , wherein the administration regimen comprises

(i) a first administration interval, which lasts for at least 4 consecutive days, wherein a first daily dose of 100 μg of Cebranopadol is orally administered on every day of the first administration interval; and

(ii) a second administration interval, which lasts for at least 4 consecutive days and directly follows the first administration interval without interruption, wherein a second daily dose of 300 μg of Cebranopadol is orally administered on every day of the second administration interval.

33. The method according to claim 32 , further comprising a third administration interval, which lasts for at least 4 consecutive days and directly follows the second administration interval without interruption, wherein a third daily dose of 400 μg of Cebranopadol is orally administered on every day of the third administration interval.

34. The method according to claim 32 , wherein each administration interval lasts for at least 5 consecutive days.

35. A method of reducing side effects associated with treatment for pain, said method comprising administering Cebranopadol according to an administration regimen comprising:

(i) a first administration interval, which lasts for at least 4 consecutive days, wherein a first daily dose of Cebranopadol is administered on every day of the first administration interval;

(ii) a second administration interval, which lasts for at least 4 consecutive days and directly follows the first administration interval without interruption, wherein a second daily dose of Cebranopadol is administered on every day of the second administration interval; and

(iii) an optional third administration interval, which lasts for at least 4 consecutive days and directly follows the second administration interval without interruption, wherein a third daily dose of Cebranopadol is administered on every day of the third administration interval;

wherein the first daily dose of Cebranopadol is lower than the second daily dose of Cebranopadol; and

wherein the second daily dose of Cebranopadol is lower than the optional third daily dose of Cebranopadol.

36. The method according to claim 35 , wherein the first daily dose of Cebranopadol is in an amount that is expected to be subtherapeutic for the patient.

37. The method according to claim 35 , wherein

the first daily dose of Cebranopadol is equal to or less than 100 μg; and/or

the first administration interval lasts for at least 4 consecutive days.

38. The method according to claim 35 , wherein the first daily dose of Cebranopadol is within the range of from 30 to 70 wt.-% of the second daily dose of Cebranopadol.

39. The method according to claim 35 , wherein

the first daily dose of Cebranopadol is within the range of from 60 to 140 μg; and/or

the second daily dose of Cebranopadol is within the range of from 160 to 240 μg.

40. The method according to claim 35 , wherein the first daily dose of Cebranopadol is within the range of from 5 to 45 wt.-% of the third daily dose of Cebranopadol and wherein the second daily dose of Cebranopadol is within the range of from 30 to 70 wt.-% of the third daily dose of Cebranopadol.

41. The method according to claim 35 , wherein the third daily dose of Cebranopadol is 95-105 μg greater than the second daily dose of Cebranopadol.

42. The method according to claim 35 , wherein

the first administration interval, the second administration interval, the optional third administration interval, and/or an optional fourth administration interval, and/or an optional fifth administration interval, and/or an optional sixth administration interval, and/or an optional seventh administration interval independently of one another last for 5 to 7 consecutive days.

43. The method according to claim 35 , wherein the administration regimen comprises

(i) a first administration interval, which lasts for at least α consecutive days, wherein a first daily dose of Cebranopadol is orally administered on every day of the first administration interval; and

(ii) a second administration interval, which lasts for at least β consecutive days and directly follows the first administration interval without interruption, wherein a second daily dose of Cebranopadol is orally administered on every day of the second administration interval;

and satisfies any of the following requirements A 2 to C 3 :

A 2

A 10

A 12

A 20

A 21

first daily

100 ± 80

100 ± 50

100 ± 50 

100 ± 20 

100 ± 20 

dose [μg]

α [days]

≥4

≥5

7 ± 3

6 ± 2

6 ± 1

second daily

200 ± 80

200 ± 50

200 ± 50 

200 ± 20 

200 ± 20 

dose [μg]

β [days]

≥4

≥5

7 ± 3

6 ± 2

6 ± 1

B 2

B 10

B 12

B 20

B 21

first daily

100 ± 80

100 ± 50

100 ± 50 

100 ± 20 

100 ± 20 

dose [μg]

α [days]

≥4

≥5

7 ± 3

6 ± 2

6 ± 1

second daily

200 ± 80

200 ± 50

200 ± 50 

200 ± 20 

200 ± 20 

dose [μg]

β [days]

≥4

≥5

7 ± 3

6 ± 2

6 ± 1

δ [days]

≥4

≥5

7 ± 3

6 ± 2

6 ± 1

C 1

C 2

C 3

first daily dose [μg]

100 ± 20

100 ± 20

100 ± 20

α [days]

≥4

≥5

≥6

second daily dose [μg]

200 ± 20

200 ± 20

200 ± 20

β [days]

≥4

≥5

≥6

44. The method according to claim 35 , wherein the pain is

acute pain or chronic pain; and/or

nociceptive pain or neuropathic pain; and/or

postoperative pain, malignant pain, and/or inflammatory pain.

45. The method according to claim 35 , wherein the administration regimen comprises

(i) a first administration interval, which lasts for at least 4 consecutive days, wherein a first daily dose of 100 μg of Cebranopadol is orally administered on every day of the first administration interval; and

(ii) a second administration interval, which lasts for at least 4 consecutive days and directly follows the first administration interval without interruption, wherein a second daily dose of 200 μg of Cebranopadol is orally administered on every day of the second administration interval.

46. The method according to claim 45 , further comprising a third administration interval, which lasts for at least 4 consecutive days and directly follows the second administration interval without interruption, wherein a third daily dose of 300 μg of Cebranopadol is orally administered on every day of the third administration interval.

47. The method according to claim 45 , wherein each administration interval lasts for at least 5 consecutive days.

48. The method according to claim 35 , wherein the administration regimen comprises

(i) a first administration interval, which lasts for at least 4 consecutive days, wherein a first daily dose of 100 μg of Cebranopadol is orally administered on every day of the first administration interval; and

(ii) a second administration interval, which lasts for at least 4 consecutive days and directly follows the first administration interval without interruption, wherein a second daily dose of 300 μg of Cebranopadol is orally administered on every day of the second administration interval.

49. The method according to claim 48 , further comprising a third administration interval, which lasts for at least 4 consecutive days and directly follows the second administration interval without interruption, wherein a third daily dose of 400 μg of Cebranopadol is orally administered on every day of the third administration interval.

50. The method according to claim 48 , wherein each administration interval lasts for at least 5 consecutive days.