Let's talk about the muscles that control our fingers, and how that affects the ergonomics of certain chords.
There are two sets of muscles in the arm that are responsible for opening and closing the hand, connected via the tendons of the fingers. Most of these extrinsic muscles are connected to multiple tendons, and therefore pull on multiple fingers. There are also some fine motor muscles within the hand that are responsible for more nuanced finger movement, but these are much weaker (and therefore slower) than the larger extrinsic muscles.
Exercise 1: hold your hand in a relaxed, open state. Touch the tip of each finger to your palm, one finger at a time, keeping the other fingers relaxed and extended. Note how other fingers are pulled closer to the palm. The pinky especially will pull the ring finger very far down. Even so, most people can touch their pinky to the palm without the ring finger being pulled all the way to the palm, unless they are pressing the pinky down with a considerable amount of force.
What does this mean for the Twiddler? All fingers can press down independently without hand strain, though the pinky can exert the least downward force. That's good news for single-key presses, though it's advisable to keep the most frequent characters away from the pinky.
Exercise 2: hold your hand in a relaxed fist, with the tips of your fingers pressed lightly against the palm. Lift the tip of each finger away from the palm, one finger at a time, keeping the other fingers pressed against the palm. The index finger will likely be able to fully extend without pulling other fingers away from the palm (it has its own extensor muscle.) The middle and pinky will be able to partially extend. However, most people can barely pull the tip of the ring finger away from the palm without also extending the middle finger or pinky, or straining the fine muscles of the hand.
What does this mean for the Twiddler? Not all fingers can lift up independently without hand strain. Chords which keep the ring finger lifted while pressing keys with both the middle and pinky finger are particularly difficult. While these chords can be improved over time by strengthening the fine muscles of the hand, this difficulty is caused by anatomical limits of the large muscles that extend our fingers, and cannot be entirely mitigated.
Exercise 3: with the Twiddler, try pressing these chords: MMMM, MMM0, 0MMM, MM00, 0MM0, 00MM, M0M0, M0MM, M00M, MM0M, 0M0M. Pay attention to the tension in your hand. Can you feel a difference, particularly in the last two chords? Is 0MMM easier to press than 0M0M, even though it uses more buttons?
Tl;dr: To avoid strain, limit the frequency of chords which press buttons with both the middle finger and pinky, but not the ring finger. These chords are not slower/harder than others because you haven't practiced enough, but because of the physical limitations of your body.