• Percent Change from Baseline in Mean 24-Hour Pain Intensity as Assessed by NPS Score to the End of Part A (Week 15) [ Time Frame: Baseline to Week 15 ]
  The 24-hour average pain intensity (NPS, an 11-point scale, 0-10, 0= no pain to 10 = most pain imaginable) will be calculated from current pain intensity scores collected 3 times a day as measured by the electronic pain diary daily during Parts A and B. Pain intensity will be evaluated on the affected limb. If more than 1 limb is involved, the participant and the investigator will determine which limb is the most problematic and the pain will be evaluated for that limb throughout the study.
• Percentage of Participants with Response at the End of Part A (Week 15) [ Time Frame: Week 15 ]
  Response is defined as ≥ 30% improvement on the 24-hour pain intensity assessed by NPS score. The 24-hour average pain intensity (NPS, an 11-point scale, 0-10, 0= no pain to 10 = most pain imaginable) will be calculated from current pain intensity scores collected 3 times a day as measured by the electronic pain diary daily during Parts A and B. Pain intensity will be evaluated on the affected limb. If more than 1 limb is involved, the participant and the investigator will determine which limb is the most problematic and the pain will be evaluated for that limb throughout the study.
• Change from Baseline of Mean Total Score of the 29-item Patient-Reported Outcomes Measurement Information System (PROMIS-29) Version 2 at the End of Part A (Week 15) [ Time Frame: Baseline to Week 15 ]
  The PROMIS-29 (version 2), a generic health-related quality of life survey, assesses each of the 7 PROMIS domains (depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, and ability to participate in social roles and activities) with 4 questions per domain. The questions are ranked on a 5-point Likert scale. The scale ranges from 1-5 in each domain: depression (1=never and 5=always); anxiety (1=never and 5=always); physical function (1=unable to do and 5 =without any difficulty); pain interference (1=not at all and 5=very much); fatigue (1=not at all and 5=very much); sleep disturbance (1=very much and 5=not at all); ability to participate in social roles and activities (1=always and 5=never).
• Percent Change from Baseline of Mean Total Score of PROMIS-29) Version 2 at the End of Part A (Week 15) [ Time Frame: Baseline to Week 15 ]
  The PROMIS-29 (version 2), a generic health-related quality of life survey, assesses each of the 7 PROMIS domains (depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, and ability to participate in social roles and activities) with 4 questions per domain. The questions are ranked on a 5-point Likert scale. The scale ranges from 1-5 in each domain: depression (1=never and 5=always); anxiety (1=never and 5=always); physical function (1=unable to do and 5 =without any difficulty); pain interference (1=not at all and 5=very much); fatigue (1=not at all and 5=very much); sleep disturbance (1=very much and 5=not at all); ability to participate in social roles and activities (1=always and 5=never).
• Change From Baseline of Mean Patient Global Impression of Change (PGIC) Scale at the End of Part A (Week 15) [ Time Frame: Baseline to Week 15 ]
  The PGIC is a 7-point Likert scale to address the following question: Since beginning treatment at this clinic would you describe any changes (if any) in activity, limitations, symptoms, emotions and overall quality of life related to your painful condition compared to before treatment? Very much improved; moderately improved; slightly improved; no change; slightly worse; moderately worse; very much worse.
• Percent Change From Baseline of Mean PGIC Scale at the End of Part A (Week 15) [ Time Frame: Baseline to Week 15 ]
  The PGIC is a 7-point Likert scale to address the following question: Since beginning treatment at this clinic would you describe any changes (if any) in activity, limitations, symptoms, emotions and overall quality of life related to your painful condition compared to before treatment? Very much improved; moderately improved; slightly improved; no change; slightly worse; moderately worse; very much worse.
• Change From Baseline of Mean CRPS Severity Score (CSS) at the End of Part A (Week 15) [ Time Frame: Baseline to Week 15 ]
  Signs and symptoms reflecting the sensory, vasomotor, sudomotor/edema, and motor/trophic disturbances of CRPS have been incorporated into a clinically feasible CSS. Signs and symptoms include relevant features of CRPS that are scored for their presence (1) or absence (0), eg, dystrophic changes to hair and nails, decreased range of motion, and motor weakness comprise the motor/trophic features of CRPS. Total CSS is a 16-point score with 8 signs and 8 symptoms.
• Percent Change From Baseline of Mean CSS at the End of Part A (Week 15) [ Time Frame: Baseline to Week 15 ]
  Signs and symptoms reflecting the sensory, vasomotor, sudomotor/edema, and motor/trophic disturbances of CRPS have been incorporated into a clinically feasible CSS. Signs and symptoms include relevant features of CRPS that are scored for their presence (1) or absence (0), eg, dystrophic changes to hair and nails, decreased range of motion, and motor weakness comprise the motor/trophic features of CRPS. Total CSS is a 16-point score with 8 signs and 8 symptoms.

The drug being tested in this study is called TAK-935. TAK-935 is being tested to treat people with chronic complex regional pain syndrome (CRPS). This study will look at the efficacy, safety, and tolerability of TAK-935 as an adjunctive therapy in participants with CRPS.

The study will enroll approximately 24 patients. Participants will be randomly assigned (by chance, like flipping a coin) in 2:1 ratio to one of the two treatment groups-which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need):

TAK-935 100 mg tablets, 100, 200 or 300 mg BID Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient

Participants will receive 100 mg TAK-935 tablets or placebo-matching TAK-935 tablets, BID for Week 1, 2x100 mg TAK-935 tablets or placebo-matching TAK-935 tablets, BID for Week 2 and followed by 3x100 mg TAK-935 tablets or placebo-matching TAK-935 tablets, BID for Week 3. Dose will be uptitrated based on safety and tolerability in titration period. Participants will continue to receive the same dose in maintenance period. Dose adjustments during maintenance period may take place due to safety and tolerability.

Participants will then enter Part B (optional) or taper period. In Part B all participants will receive TAK-935 2x100 mg tablets, BID for 1 Week, followed by TAK-935 3x100 mg tablets, BID for 1 Week. Dose will be uptitrated/downtitrated based on safety and tolerability in titration period (Part B), participants will continue to receive the same dose in maintenance period (Part B) and followed by a taper period.

This multi-center trial will be conducted in United Kingdom. The overall time to participate in this study is approximately 36 weeks. Participants will make multiple visits to the clinic and will be contacted by telephone 15 days after last dose of study drug for a follow-up assessment.

• Drug: TAK-935
  TAK-935 Tablets
• Drug: TAK-935 Placebo
  TAK-935 placebo-matching tablets

• Experimental: Part A: TAK-935
  Part A (Double blind titration period): Tablets, TAK-935, 100 mg, orally, twice daily (BID) for Week 1, followed by tablets, TAK-935, 200 mg, orally, BID for Week 2, further followed by tablets, TAK-935, 300 mg, orally, BID for Week 3. Dose will be uptitrated every week based on safety and tolerability. Part A (Double blind maintenance period): Tablets, TAK-935 300 mg, orally BID for 12 weeks. Dose adjustments during maintenance period may take place due to safety and tolerability. Taper period (if participant does not continue to Part B): Dose of TAK-935 to be reduced to next lower dose every 3 days (maximum 6 days) till TAK-935 is discontinued.
  Intervention: Drug: TAK-935
• Placebo Comparator: Part A: Placebo
  TAK-935 placebo-matching tablets, orally, BID for Weeks 1, 2 and 3 in Double blind titration period. TAK-935 placebo-matching tablets, orally BID for 12 weeks in Double blind maintenance period. Taper period (if participant does not continue to Part B): Dose of TAK-935 placebo-matching tablets to be reduced to next lower dose every 3 days (maximum 6 days) till TAK-935 is discontinued.
  Intervention: Drug: TAK-935 Placebo
• Experimental: Part B: TAK-935
  Part B (Optional, Open label extension: titration period all participants to receive TAK-935): Tablets, TAK-935, 200 mg, orally, BID up to 1 week followed by tablets, TAK-935, 300 mg, orally, BID for up to 1 week. Dose will be uptitrated every week based on safety and tolerability. Part B (Open label extension: maintenance period): Tablets, TAK-935 300 mg, orally BID for 12 weeks. Dose adjustments during maintenance period may take place due to safety and tolerability. Taper period: Dose of TAK-935 to be reduced to next lower dose every 3 days (maximum 6 days) till TAK-935 is discontinued.
  Intervention: Drug: TAK-935

Inclusion Criteria:

1. Participant meets the Budapest clinical diagnosis of complex regional pain syndrome (CRPS) at the screening visit and is at least 6 months since onset of symptoms.
2. Participant's pain medications and nondrug treatments must be stable (regimented per prescription) for 1 month prior to screening and remain stable throughout Part A.
3. Participant agrees to use a single previously prescribed rescue medication within the prescribed dose during Part A of the study and to record the daily use of these medications.
4. Participant must have an average 24-hour pain intensity score ≥4 and ≤9 on the 24-hour average pain intensity numeric pain scale (NPS) during screening/baseline. This score will be calculated by averaging the daily 24 hour pain intensity scores for the past seven days prior to randomization. The participant must have daily 24-hour pain intensity scores recorded for at least 6 of the past 7 days.

Exclusion Criteria:

1. Currently receiving intravenous (IV) or oral ketamine, history of IV or oral ketamine use within the past 6 weeks prior to screening, or planned use of IV or oral ketamine during this study.
2. Participant is receiving chronic opioid treatment at a dose that has not been stable 28 days prior to screening.
3. Participant is receiving chronic opioid treatment >160 mg of morphine equivalent per day.
4. Participant has a positive drug screen for phencyclidine, amphetamine/ methamphetamine, or cocaine at screening. Cannabis is allowed.
5. Has cataracts based on investigator opinion.
6. Participant is positive for hepatitis B or hepatitis C infection at screening. (Note that participants who have been vaccinated against hepatitis B [hepatitis B surface antibody {Ab}-positive] who are negative for other markers of prior hepatitis B infection [eg, negative for hepatitis B core Ab] are eligible. Also, note that participants who are positive for hepatitis C Ab are eligible if they have a negative hepatitis C viral load by quantitative polymerase chain reaction).